Molecular mechanisms of acute systemic responses and

kidney-specific pathophysiology

Authors: Forough Chelangarimiyandoab, Jean-Philippe C. Lavoie, Nicolas Flamand, Emmanuelle Cordat, Sylvie Breton

Abstract

INTRODUCTION

Although ancient medical texts mention inflammation, the Roman physician Cornelius Celsus in the 1st century AD is recognized as the first to describe its clinical symptoms, which include redness, swelling, heat, and pain (1). Later, Augustus Waller (1846) and Julius Cohnheim (1867) uncovered the underlying physiology of these four primary signs of inflammation by identifying leukocyte emigration from blood vessels and other vascular changes during the inflammatory response. By examining living tissues under the microscope, Cohnheim noted vasodilation, plasma leakage, and the migration of leukocytes from blood vessels into the tissue. In 1858, Rudolph Virchow introduced “disturbance of function” as a fifth primary sign associated with all inflammatory processes, contrasting with the four signs described by Celsus, which were limited to acute inflammation related to wounds and infections. A significant milestone was Elie Metchnikoff’s discovery of phagocytosis and his development of the cellular immunity theory in 1892. At the same time, Paul Ehrlich was working on the humoral theory of immunity, building on the serum therapy discoveries in 1890. The discovery of complement by Jules Bordet in 1896 further reinforced the role of serum components in immunity. Ultimately, Robert Koch and Louis Pasteur established the germ theory of disease in the late 19th century, a breakthrough that was instrumental in identifying microbial agents as key triggers of acute inflammation.

It is now known that inflammation is a complex immune response that arises in reaction to various triggers, such as infections, cellular damage, and exposure to toxic agents (2). It serves to eliminate harmful stimuli while initiating the healing process. Inflammation is classified into two primary types—acute and chronic—based on its duration and distinct pathological characteristics (3). If the inflammatory trigger is not resolved by the acute inflammatory response or persists for other reasons, the failure to initiate the resolution phase can lead to chronic inflammation (1). This prolonged inflammatory state is associated with the development of various serious conditions, including tumors, neurodegenerative diseases, autoimmune disorders, diabetes, cardiovascular diseases, and fibrosis (1, 4). Although this review focuses on acute inflammation, readers seeking an in-depth understanding of chronic inflammation are encouraged to refer to the review by Lawrence and Gilroy (5).

ACUTE INFLAMMATION

Typically, during acute inflammatory responses, cellular and molecular processes work together to quickly mitigate potential injury or infection (2). Inflammation can arise from either infectious or noninfectious causes (2) (Fig. 1). In sterile inflammation, the body initiates an immune response in the absence of pathogens, triggered by damage-associated molecular patterns (DAMPs), which are released by injured cells (6). Conversely, nonsterile inflammation is driven by pathogen-associated molecular patterns (PAMPs), which are molecules from infectious agents that activate immune responses (6).

The innate immune system is the primary driver of acute inflammation in response to infections or tissue damage (7). This recognition is mediated by pattern recognition receptors (PRRs) that are activated by PAMPs and DAMPs. At present, several families of PRRs have been identified. These include transmembrane proteins, such as Toll-like receptors (TLRs) and C-type lectin receptors, as well as cytoplasmic proteins including retinoic acid-inducible gene (RIG)-I-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the absent in melanoma 2-like receptors, and DNA sensors such as cyclic GMP-AMP synthase (7–9). PRRs are not limited to macrophages and dendritic cells; they are also found in all immune cells (7).

TLRs are highly conserved mammalian PRRs that play critical roles in activating the inflammatory response. They were the first PRRs to be identified and are the most extensively characterized (2, 10). This family consists of 10 members (TLR1–TLR10) in humans and 12 members (TLR1–TLR9, TLR11–TLR13) in mice (10). They are type I transmembrane proteins with three structural a leucine-rich repeat motif responsible for recognizing molecular patterns, a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor domain that interacts with signal transduction adaptors to initiate signaling. Cell-surface TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10) primarily detect microbial membrane components such as lipids, lipoproteins, and proteins, whereas endosomal TLRs (TLR3, TLR7, TLR8, TLR9, and TLR11–TLR13) sense nucleic acids of microbial origin as well as self-derived nucleic acids released during tissue injury.

PAMP-MEDIATED INFLAMMATION

Key PAMPs include microbial nucleic acids such as DNA with unmethylated cytidine-phosphate-guanine (CpG) motifs, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), 5′-triphosphate RNA, lipoproteins (LP), surface glycoproteins (GP), and membrane components, including peptidoglycans, lipoteichoic acid (LTA), lipopolysaccharides (LPS), and glycosylphosphatidylinositol (GPI) (11).

Several TLRs recognize PAMPs. These include TLR4, which detects gram-negative bacteria by recognizing LPS, a component located on the outer membrane of these microorganisms (12). In addition to recognizing PAMPs, TLR4 can also be activated by endogenous molecules, such as intracellular peptides, glycoproteins, and phospholipids, which are released during tissue damage (13). TLR2 recognizes a broad range of microbial components, including gram-positive bacteria, peptidoglycan, yeast zymosan, and mycobacterial ara-lipoarabinomannan (a critical cell envelope LPS), highlighting its role in promoting infection clearance (12, 14). Both of these TLRs are predominantly expressed on the plasma membrane of monocytes/macrophages, and neutrophils. Human TLR3, found in dendritic cells, detects dsRNA, a molecular marker of RNA viruses (15). Previous studies demonstrated the necessity of TLR5 for the recognition of flagellin, which is a key structural component of bacterial flagella that acts as a virulence factor in both Gram-negative and Gram-positive bacteria (16, 17). TLR5 also collaborates with TLR4 in the antibacterial immune response (16). TLR7, present in dendritic cells and B cells, recognizes single-stranded RNA (ssRNA) derived from RNA viruses (18). TLR8, closely related to TLR7, also recognizes ssRNA and is mainly expressed in myeloid dendritic cells and monocytes. TLR9 not only detects single-stranded DNA containing unmethylated CpG motifs from bacteria or viruses, but it also identifies DNA fragments released from host cells, promoting sterile inflammation linked to autoimmune disorders (19, 20).

DAMP-MEDIATED INFLAMMATION

DAMPs can be categorized into several classes according to their source (21). They are released in response to tissue stress, injury, or cell death, and trigger inflammatory responses through various pathways (22). Key DAMPS include proteoglycans, hyaluronan (HA), heparan sulfate, fibronectin, fibrinogen, tenascin C, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1), uridine diphosphate (UDP)-sugars, the S100 proteins, and heat shock proteins (HSPs) (21–30). Certain molecules, typically sequestered within the extracellular matrix (ECM) under normal conditions, can be proteolytically released after tissue injury, where they function in their soluble form as DAMPs (21). Proteoglycans are the most well-characterized ECM-derived DAMPs. Among them, biglycan and decorin are small leucine-rich proteoglycans that act as endogenous ligands for TLR2 and TLR4, triggering sterile inflammation. In addition, the biglycan-mediated interaction of TLR2/4 receptors stimulates the synthesis and maturation of interleukin-1 beta (IL-1β), a proinflammatory master cytokine, through the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and caspase-1 (31). Conversely, soluble decorin activates TLR2/4 signaling and blocks transforming growth factor beta-1 (TGF-β1), promoting a proinflammatory environment that may help treat tumors (21). Versican, a chondroitin sulfate proteoglycan, binds the TLR2/TLR6 heterodimer and its adaptor CD14, promoting cancer metastasis (21). Low molecular weight HA fragments also activate TLR2/4, driving inflammation, angiogenesis, and cancer metastasis. In addition, heparan sulfate, fibronectin, fibrinogen, and tenascin C interact with TLR4 (22).

Alongside ECM-derived DAMPs, a diverse range of intracellular danger molecules is released during necrosis or apoptosis, and can function as extracellular soluble DAMPs (21). Mitochondrial DAMPs, such as mtDNA, formyl peptides (FPs), adenosine triphosphate (ATP), and transcription factor A (Tfam), along with intact mitochondria, can function as danger signals (23–25).

Autophagy plays a crucial role in the release and degradation of DAMPs, such as chromatin-associated HMGB1, ATP, and DNA, across various cell types in response to stress or injury (26). DNA can be released from dying cells, acting as ligands for TLRs (21, 32, 33). HMGB1, previously noted as an autophagy-related DAMP, functions both as a nuclear factor and as a secreted protein (34). This nonhistone nuclear protein can move out of cells during immune cell activation and cell death (35). It interacts with TLR4 and can also bind to cytokines to activate other receptors. Extracellular ATP (eATP) functions as a DAMP by signaling through the purinergic P2 receptor family present on different immune and nonimmune cells (36, 37). This family includes ligand (ATP)-gated ionotropic P2X receptors (P2XR) and G protein-coupled metabotropic P2Y receptors (P2YR) (38). P2XRs are trimeric ion channels that are permeable to Na^+^, K^+^, and Ca^2+^ and open upon interaction with eATP (39). Within this group, the expression of the P2X7 receptor is linked to inflammation, survival, proliferation, angiogenesis, and metastasis (38, 40, 41). This receptor exhibits a biphasic ATP short stimulation allows Na^+^ and Ca^2+^ influx, while prolonged activation opens a nonselective pore for molecules <900 Da. ATP released from injured cells acts as a danger signal by targeting P2X7 receptor, enhancing immune responses through cytokine secretion (42–44). P2X7 is located in immune cells, glial cells, epithelial cells, and endothelial cells. ATP signaling through P2X7 receptor triggers inflammasome activation, promoting the maturation and release of proinflammatory cytokines IL-1β and interleukin-18 (IL-18), as well as the generation of oxygen and nitrogen radicals (44). In contrast, P2Y receptors exhibit diverse nucleotide ligand selectivity, with P2Y11 receptor being the only receptor primarily responsive to ATP, whereas other P2Y receptors preferentially bind to adenosine diphosphate, UDP, uridine triphosphate, or UDP-sugars as their main agonists (38). Among these, UDP-sugars not only play a critical role in glycosylation but also function as DAMPs, within the group of cytosolic DAMPs (21, 27–30, 45). They act as potent agonists of the proinflammatory P2Y14 receptor following their release from injured cells (27–30). P2Y14 is abundantly expressed in immune cells and various tissues, including the brain, gastrointestinal tract, kidneys, lungs, and the female and male reproductive tracts (46, 47). Similarly, cytosolic uric acid, as a cytosolic DAMP, stimulates an acute inflammatory response to sterile cell death in mice (48). It is normally present in cells, and its concentration rises in response to cellular injury (49). In addition, the S100 proteins, a diverse group of calcium-binding proteins, can be released by phagocytes and are also involved in inflammation and fibrosis through PRR activation (50). Endogenous molecules, such as HSPs, released from injured or dying cells act as danger signals for the innate immune system by activating TLRs (51).

INFLAMMATORY DOWNSTREAM MEDIATORS

DAMP- and PAMP-triggered inflammation is tightly controlled by a variety of mediators and regulators, including growth factors, cytokines, complement proteins, and peptides (52). Cytokines are essential regulators of inflammation, playing a role in both acute and chronic inflammatory processes (53). These low molecular weight glycoproteins are produced and released by a wide variety of cells, including immune cells such as macrophages, T and B lymphocytes, mast cells, as well as fibroblasts, endothelial cells, and other stromal cells (52). Proinflammatory cytokines promote inflammation, whereas anti-inflammatory cytokines work to suppress it (2). Inflammatory cytokines, categorized as interleukins (ILs), colony-stimulating factors (CSFs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors (TGFs), and chemokines (a class of cytokines with chemoattractant properties), are produced mainly to recruit and activate leukocytes to sites of infection or injury (52, 53). Major proinflammatory cytokines include interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) (52).

Interleukins

The IL-1 family includes both pro- and anti-inflammatory cytokines (53). Among its proinflammatory members, IL-1α and IL-1β are central drivers of inflammation. They are produced by various cell types, including monocytes, macrophages, neutrophils, hepatocytes, and tissue macrophages. Although IL-1α is constitutively expressed in many cells, IL-1β expression is primarily induced in response to microbial signals and can also self-stimulate its production. IL-1β requires activation through cleavage by IL-1-converting enzyme or caspase-1 within the inflammasome complex. In contrast, IL-1α is active in both its precursor and mature forms, allowing it to function locally within cells. Both cytokines bind to the IL-1 receptor to drive inflammation by promoting immune cell recruitment and activation. Anti-inflammatory members of this family, such as the IL-1 receptor antagonist, help regulate this response by blocking receptor activation, preventing excessive inflammatory damage.

IL-6 is a multifunctional cytokine produced by a wide range of cells, including immune cells, fibroblasts, endothelial cells, keratinocytes, hepatocytes, and bone marrow cells (53). It plays a significant role in immune regulation by promoting B-cell maturation into antibody-producing plasma cells, activating T cells, and regulating T helper cell type 2 (Th2) and T regulatory cell (Treg) differentiation (54–56). This cytokine signals through the IL-6 receptor (IL-6R) and the gp130 coreceptor (57).

TNF-α

This mediator is a potent inflammatory cytokine initially identified for its role in inducing tumor cell necrosis (58). Secreted primarily by activated macrophages, TNF-α plays a central role in driving the inflammatory response of the innate immune system by promoting cytokine production, inducing the activation or expression of adhesion molecules, and enhancing growth (59–63). TNF-α promotes the proliferation of normal cells, exhibits cytolytic or cytostatic effects on tumor cells, and induces inflammatory, antiviral, and immunoregulatory responses (64). In addition, TNF-α plays roles in lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF-α signals through two main TNFR1, found broadly across tissues and mediating proinflammatory responses, and TNFR2, mainly expressed by leukocytes and endothelial cells (63, 65, 66).

Lipids

In addition to protein mediators such as cytokines and chemokines, lipids also act as mediators of inflammation along with their other functions (67). Indeed, lipids are ubiquitous, serving critical roles in ensuring the structural integrity as key components of cell membranes, and in regulating a wide range of physiological and pathophysiological processes. They have important roles in maintaining homeostasis (cell growth and death) and as mediators of host defense (inflammation and infection). In fact, they have different roles in the inflammatory response, contributing to both the onset and the resolution of inflammation. In certain instances, they have been considered as the principal drivers in the development and progression of inflammatory diseases.

There are numerous metabolic pathways leading to the synthesis of bioactive lipids involved in the inflammatory response (Fig. 2). These pathways involve three types of enzymes, namely, the lipoxygenases (LOXs), the cyclooxygenases (COXs), and the cytochrome P450 enzymes (CYP450s). Their main substrates are polyunsaturated fatty acids (PUFAs), such as, but not restricted to, arachidonic acid (AA; 4 n-6), eicosapentaenoic acid (20:5 n-3), and docosahexaenoic acid (22:6 n-3). LOXs catalyze the oxidation of PUFAs leading to the synthesis of fatty acid hydroperoxides, which are precursors of different oxylipins [e.g., hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs)]. COXs catalyze, together with prostaglandin (PG) and thromboxane (TX) synthases, the production of PGs [e.g., prostaglandin E2 (PGE2)] and TXs [e.g., Thromboxane A2 (TXA2)], from PUFAs. CYP450s produce fatty acid epoxides [e.g., epoxyeicosatrienoic acids (EETs)] and some hydroxylated species (e.g., HETEs, dihydroxyeicosatrienoic acids) due to their ω-hydroxylase activity (68, 69). However, some lipid mediators also arise from nonenzymatic oxidation. Noteworthy, some lipid mediators exclusively originate through nonenzymatic pathways, notably isoprostanes, which are structurally analogous to PGs, and levuglandins. Finally, LOXs, COXs and CYP450s can also participate in the metabolism of other types of PUFA-containing lipids, such as monoacylglycerols and N-acylethanolamines (reviewed in Ref. 70).

Bioactive lipids play numerous roles in inflammation. These lipids can either act as chemoattractants [e.g., leukotriene B4 (LTB4), 5-oxo-eicosatetraenoic acid (5-KETE)], or regulate leukocyte functions (e.g., inhibition of neutrophil functions by PGE2) (71, 72). Some bioactive lipids stimulate extravascular leukocyte accumulation and degranulation (e.g., platelet-activating factor) or lead to cytokine and chemokine production (72). A few of them can also modulate vascular responses such as vasoconstriction and vasodilation (e.g., PGs) or promote platelet aggregation (e.g., TXA2) (73, 74).

Furthermore, lipid mediators exert their functions through a variety of receptors, among which are purinergic receptors. For instance, PGE2-glycerol, a cyclooxygenase-2 (COX-2) metabolite, activates the purinergic receptor P2Y6, a G protein-coupled receptor that is traditionally activated by uridine diphosphate (UDP) (75, 76). Also, UDP has been reported to activate the receptors of cysteinyl leukotrienes, a class of peptide-conjugated lipids formed from arachidonic acid (77–79). However, some cross talk previously described between lipid mediators, their receptors, and the purinergic system was later refuted. In fact, the LTB4 receptor BLT1 was originally characterized as a receptor for ATP with high affinity and named as the purinergic receptor P2Y7 (80). It has later been demonstrated that BLT1 is not modulated by purinergic ligands (81, 82). Similarly, the receptors P2Y9 and P2Y5, now designated as LPA4/GPR23 and LPA6, respectively, were originally classified within the P2Y receptor family based on phylogenetic analyses; however, subsequent studies demonstrated that their ligands are lysophosphatidic acids rather than purinergic nucleotides (77, 83, 84). Finally, some P2X and P2Y receptors significantly modulate lipid mediator synthesis and signaling (85–87). Overall, such cross talk has remained largely unexplored, despite growing evidence that the purinergic system and lipid mediators are closely related, perhaps more than anticipated.

Altogether, it is evident that bioactive lipids contribute to the Celsus’ cardinal signs of inflammation mentioned earlier. In fact, the lipid metabolism has been targeted over the last millennia to decrease symptoms of inflammation, as evidenced by the traditional use of white willow (Salix alba) bark for its anti-inflammatory properties due to its salicin content, a precursor to modern anti-inflammatory drugs (88). Since then, numerous more effective molecules have been identified and are now widely used in patient treatment. Among them are glucocorticoids (e.g., cortisone), and numerous lipid modulators, notably nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, aspirin), leukotriene receptor antagonists (e.g., montelukast), and the 5-LOX inhibitor zileuton. All these drugs are used to either decrease the effects or the synthesis of proinflammatory lipid mediators. It is, therefore, essential to deepen our understanding of lipid functions and metabolism in different organs and tissues, not only to elucidate the mechanisms underlying inflammatory diseases, but also to identify novel therapeutic strategies and optimize existing treatments.

INTRACELLULAR PROINFLAMMATORY SIGNALING PATHWAYS

Key intracellular signaling pathways activated following receptor engagement include the nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathways (89–91) (Fig. 3).

The transcription factor NF-κB plays a key role in regulating various aspects of innate and adaptive immunity and acts as a central mediator of inflammatory responses (92). This family consists of five structurally related NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its precursor p100), RelA (p65), RelB, and c-Rel (93). NF-κB activity is regulated by IκB proteins, which bind NF-κB in the cytoplasm and prevent its nuclear translocation (94). Upon cellular stimulation, IκB is phosphorylated, ubiquitinated, and degraded by the proteasome, freeing NF-κB to enter the nucleus and bind DNA. NF-κB activation occurs through two main the canonical and noncanonical pathways, each vital for immune and inflammatory regulation (92). The main triggers of canonical signaling—TNF-α, IL-1β, LPS, and antigens—activate their respective tumor necrosis factor receptor (TNFR), IL-1R, TLR, B-cell receptor (BCR), and T-cell receptor (TCR) (95). This activation triggers IκBα degradation via transforming growth factor-β-activated kinase 1 (TAK1), IκB kinase (IKK) phosphorylation, leading to NF-κB nuclear translocation, primarily with p50/RelA (92, 96). Noncanonical NF-κB signaling is initiated by stimuli such as B lymphocyte activating factor (BAFF) binding to BAFF receptor (BAFFR), CD40 ligand (CD40L) binding to CD40, lymphotoxin α/β (LT α/β) and tumor necrosis factor ligand superfamily member 14 activating LTβR, and receptor activator of NF-κB ligand (RANKL) engaging RANK, most of which are part of the TNFR superfamily (95). It relies on NF-κB-inducing kinase (NIK) to process p100 into p52, enabling the nuclear translocation of p52/RelB complex (97). NF-κB pathway controls the production of proinflammatory cytokines and the recruitment of inflammatory cells, both of which play a key role in the inflammatory response (2).

MAPKs are a family of highly conserved serine/threonine protein kinases involved in regulating essential cellular processes such as gene expression, cell survival and apoptosis, proliferation, differentiation, and responses to cellular stress and inflammation (98). Each MAPK signaling pathway, activated by extracellular stimuli like stress and cytokines, comprises three key a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and a MAPK (2, 99). MAPKKKs phosphorylate and activate MAPKKs, which subsequently phosphorylate and activate MAPKs (2). In mammals, the three primary classes of MAPKs are the extracellular signal-regulated kinases (ERKs) and the two stress-activated protein kinase c-Jun N-terminal kinase (JNK) and p38 (98, 99). In the Erk1/2 pathway, Erk1/2 activation is mediated by MAPK kinase 1/2 (MKK1/2), which is activated by Raf (2). This pathway can be triggered by various upstream signals, including TLR ligands such as LPS (via TLR4) and CpG DNA (via TLR9); EGFR ligands such as TGF-α; proinflammatory cytokines like TNF-α (via TNFR), and UDP-sugars through P2Y14 (100–103). In the JNK pathway, JNK is activated by MAPK kinase 4/7 (MKK4/7), which is activated by MEKK1/4, ASK1, and MLK3. Similarly, in the p38 pathway, p38 is activated by MAPK kinase 3/6 (MKK3/6), which is previously activated by mixed-lineage kinase 3 (MLK3), transforming growth factor-β-activated kinase (TAK), and dual leucine zipper-bearing kinase. Activated MAPKs phosphorylate diverse proteins, including transcription factors, thereby modulating inflammatory responses. The JNK and p38 pathways are predominantly triggered by inflammatory cytokines like TNF-α (binding to TNFR) and IL-1β (binding to IL-R), as well as various cellular stressors (104).

The JAK/STAT signaling pathway involves over 50 cytokines and growth factors, including hormones, interferons (IFNs), interleukins (ILs), and colony-stimulating factors (105). The four major multichain receptor families that activate JAK/STAT signaling include the interleukin-2 receptor (IL-2R), interleukin-3 receptor (IL-3R), IL-6R, and interferon receptor (IFNR) families, each recognizing distinct cytokines (106). The IL-2R family binds cytokines such as IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21, whereas the IL-3R family is associated with IL-3 and IL-5. The IL-6R family interacts with IL-6, IL-11, IL-12, IL-23, IL-27, and IL-35. Meanwhile, the IFNR family mediates responses to interferons (IFN-α, -β, and -γ) as well as IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. The JAK/STAT pathway directly mediates communication from transmembrane receptors to the nucleus in four steps: 1) Cytokines bind to their respective receptors, triggering receptor dimerization and activation of JAKs, which then phosphorylate each other and the intracellular receptor tail; 2) The phosphorylated tyrosine sites create a docking site for STAT proteins; 3) STATs are recruited, phosphorylated, and activated, enabling them to dimerize; and 4) The STAT dimers translocate to the nucleus, where they regulate gene expression (107).

CELLULAR PLAYERS

Inflammation is triggered following activation of proinflammatory pathways in immune cells as well as nonimmune resident cells. Activation of innate immune cells, including neutrophils, monocytes/macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils, and innate lymphoid cells, provides rapid, nonspecific defense, and activation of adaptive immune cells, such as T and B lymphocytes, mediates specific and long-lasting immunity (2, 108, 109). Nonimmune cells, including epithelial cells, endothelial cells, fibroblasts, and platelets, also contribute critically to immune regulation (110–113).

Among leukocytes, neutrophils are often the first responders recruited to inflammatory sites and are equipped with antimicrobial functions such as phagocytosis, production of reactive oxygen species, cytokine secretion, and release of neutrophil extracellular traps (114–116). Although essential for pathogen clearance, excessive neutrophil activation can damage host tissue (114). Monocytes and macrophages further regulate the inflammatory response through phagocytosis, mediator release, and coordination of tissue repair (117, 118). Importantly, macrophage polarization is not strictly while M1 macrophages are generally pro-inflammatory, and M2 macrophages are associated with tissue repair, some M2 subsets also exert proinflammatory functions depending on the disease context (117). Dendritic cells integrate innate and adaptive responses by sensing danger signals and presenting antigens to T cells (119). Natural killer cells also contribute by killing infected or transformed cells while producing cytokines that amplify inflammation (120). Mast cells and basophils enhance vascular permeability and leukocyte recruitment by releasing histamine, prostaglandins, and leukotrienes (108, 121). Eosinophils, when activated through cytokine, immunoglobulin, or complement receptor engagement, release various mediators like cytokines, chemokines, lipid mediators, and cytotoxic proteins involved in defense against parasitic infections (122). T and B lymphocytes exert dual Th1/Th17 T cells and antibody-secreting B cells drive inflammation, whereas Tregs and Bregs restrain it through cytokines like IL-10 (123–126). Circulating nonimmune cells can also contribute to inflammation. For example, platelets not only function in hemostasis but also release cytokines and chemokines that shape inflammatory responses (113, 127, 128).

Resident tissue cells also participate in acute inflammation responses. Endothelial cells regulate leukocyte trafficking and inflammatory mediator release, with dysfunction linked to severe outcomes in conditions such as COVID-19 (129, 130). Fibroblasts influence the inflammatory milieu by secreting cytokines and growth factors, and depending on the context, they may promote resolution or fibrosis (111, 131, 132). Finally, epithelial cells act as both a barrier and active mediators, releasing cytokines, chemokines, and antimicrobial peptides (AMPs) in response to damage- and pathogen-associated signals (133, 134).

The kidneys are highly susceptible to damage caused by inflammation (135). Renal epithelial cells are sensors and initiators of inflammation in response to tissue damage or infection, linking local danger sensing to systemic immune activation (110, 136). In the subsequent sections of this paper, we will focus specifically on the role of kidney epithelial cells in inflammation, highlighting their unique functions and contributions in renal immunity and tissue damage.

PATHOPHYSIOLOGY OF RENAL INFLAMMATORY DISEASES

Inflammatory diseases, whether infectious or not, involve an accumulation of inflammatory cells that, along with endothelial cells and fibroblasts, release mediators and enzymes, causing tissue damage (137). They encompass a wide range of conditions driven by inflammation in various organs (2, 138). These include, but are not limited to, allergies, asthma, autoimmune disorders, glomerulonephritis, celiac disease, diabetic nephropathy, pulmonary fibrosis, ischemia-reperfusion injury, inflammatory bowel disease, ulcerative colitis, hepatitis, and transplant rejection (138).

The main functions of the kidneys include eliminating metabolic waste and toxins, regulating fluid and electrolyte balance, maintaining blood pH, and supporting systemic gluconeogenesis (139). These functions are orchestrated in the nephron, composed by the glomeruli and specialized tubular segments, including the proximal tubule, loop of Henle, distal tubule, connecting segment, and collecting duct. Due to their key role at filtering the blood, they are rapidly exposed to DAMPs and PAMPs that are produced by distant organs. This might explain the high prevalence of acute kidney injury (AKI) in intensive care unit patients, regardless of the cause of hospitalization. AKI may also occur following local renal ischemia-reperfusion injury, which happens, for example, during surgeries requiring cardio-pulmonary bypass, a procedure known to reduce renal blood flow, as well as during a direct surgery to the kidney or during transplantation (140). AKI, characterized by a rapid decline in glomerular filtration rate, accumulation of nitrogenous waste products like urea and creatinine, and disruptions in acid-base and fluid-electrolyte balance, is linked to inflammation (136, 141). AKI can progress to chronic kidney disease (CKD) or end-stage renal disease. It is strongly associated with metabolic disorders like diabetic nephropathy, where conditions such as insulin resistance and obesity worsen kidney damage (142). In autoimmune diseases such as lupus nephritis, the deposition of immune complexes in the glomeruli initiates a cascade of inflammatory responses (143, 144). In addition, urinary tract infections (UTIs), among the most prevalent infections, can lead to sepsis or septic shock, which may cause a sudden decline in renal function (145, 146). Infections can impact different segments of the urinary tract, categorized as urethritis (urethra), cystitis (bladder), and pyelonephritis (kidneys) (147). They are primarily caused by pathogens such as gram-negative bacteria, with uropathogenic Escherichia coli (UPEC) being the most prevalent (148). Ascending UPEC colonizes the bladder, forming biofilms and intracellular bacterial communities, and may migrate to the kidneys, causing tissue damage and impairing renal function (149).

Several types of immune cells populate the kidney, where they contribute to either the deterioration or protection of kidney function following injury, determining recovery from AKI or development of fibrosis leading to CKD (150–154). The early steps of renal inflammation include the rapid recruitment of circulating innate immune cells into the renal tissue, further exacerbating kidney damage (27, 136). These first events are triggered by damaged tubular epithelial cells and endothelial cells, which release DAMPs and PAMPs that in turn attract and activate newly recruited neutrophils and monocytes. Complex interactions between immune cells and kidney epithelial cells contribute to renal outcomes (154). In particular, recent research highlighted the role of proximal tubule cells and collecting duct type A intercalated cells (ICs) in initiating innate immune responses and contributing to renal inflammation (110). Because the vast majority of studies exploring inflammation in the kidney were performed in male mice, most of the publications discussed in the remaining sections describe renal inflammation in males. Thanks to the increased awareness regarding sex differences in kidney function, clearly needed studies are currently ongoing to further understand the mechanisms underlying the physiology and pathophysiology of female versus male kidneys.

RENAL EPITHELIAL CELLS AND STERILE INFLAMMATION

Epithelial cells form the first barrier against pathogens and harmful molecules, and their role in the activation of innate immunity is now broadly recognized. Upon injury, they secrete several mediators including histones, DNA fragments, heat shock proteins, uric acid, HMGB1, uromodulin, ATP, and UDP-sugars that trigger sterile renal inflammation (154).

Purinergic Receptors

Although extracellular ATP is involved in the physiological regulation of kidney function, it can also trigger renal inflammation through activation of P2 receptors (155–157) (Fig. 4). For example, P2X7 activation in kidney resident immune cells or in tubular epithelial cells participates in renal inflammation in ischemia-induced AKI (152, 153). Another mechanism involved in renal inflammation is related to the P2Y2 receptor located in proximal tubules. In contrast to other P2 receptors, such as P2X7 and P2Y14 whose inhibition reduces kidney injury, activation of P2Y2 was shown to protect against tubular apoptosis and inflammation in ischemia-induced AKI (158).

Proximal Tubules

Proximal tubule cells are the most affected renal epithelial cells following ischemia-reperfusion injury because they highly depend on mitochondrial ATP to perform their function. Damaged proximal tubules express kidney injury molecule-1 (KIM-1) (159) (Fig. 4). KIM-1 facilitates the clearance of apoptotic and necrotic cells through efferocytosis, transforming proximal tubule cells into semiprofessional phagocytes (160–162). One of the protective mechanisms of KIM-1 include preventing DAMP release, inhibiting NF-κB signaling, and degrading the proapoptotic receptor NUR77 (163–165). However, some studies suggest that KIM-1 may worsen injury by recruiting immune cells and enhancing inflammation under certain conditions (166, 167).

Cross Talk between Proximal Tubules and Collecting Ducts via the P2Y14

Pathway

Damaged proximal tubules rapidly release UDP-glucose, which then reaches the lumen of the collecting duct. In this segment, type A ICs express the proinflammatory receptor P2Y14 (GPR105) in their apical membrane (27, 47, 168) (Fig. 4). The UDP-glucose/P2Y14 interaction in these cells activates the MEK1/2-ERK1/2 signaling pathway. This leads to the expression of proinflammatory chemokines and cytokines, including IL-β, Cxcl1 (KC, GRO-α), Cxcl2 (MIP-2α), Cxcl3 (MIP-2β), and Ccl2 (MCP-1), which recruit and activate neutrophils and monocytes to the kidney (27, 47, 110, 136). The influx of these immune cells exacerbates tubular injury and hinders the repair process (136). P2Y14 inhibition or specific deletion of P2Y14 in ICs attenuated these effects. In cardiac surgery patients, elevated levels of urinary UDP-glucose are predictors of AKI supporting the participation of the UDP-glucose/P2Y14 pathway in the etiology of ischemia-induced AKI (27). Thus, inhibition of P2Y14 is a promising strategy that targets the early immune response to kidney injury, and is supported clinically by the availability of urinary UDP-glucose as a corresponding biomarker.

Following their recruitment to the kidney, neutrophils are activated by HMGB1 released from necrotic tubules (169). HMGB1 binds TLR4 present on neutrophils and triggers the formation of NETs, which further damage kidney tubules through oxidative stress and endothelial dysfunction.

Lipid Mediators

Few studies have explored the roles of lipid mediators in ischemia-induced AKI. A recent study showed that prostacyclin (PGI2) levels are increased in the kidney after ischemia-induced AKI and that the genetic deletion of the PGI synthase worsened AKI compared with control mice (170, 171). This is likely due to the role of PGI2 in maintaining renal blood flow, as it acts as both a vasodilator and an inhibitor of platelet aggregation. This paves the way for using prostacyclin analogs and the modulation of its receptor to prevent ischemic-induced AKI. Iloprost and treprostinil, two prostacyclin analogs, have been tested in mice and rats, respectively (170, 172). They both attenuated kidney damage and improved renal function compared with untreated animals. In rats, treprostinil also reduced the expression of cytokines (IL-1β, IL-6, and CCL2) and intracellular adhesion molecule (ICAM)-1.

Another prostaglandin, PGE2, is naturally present in kidney tissue and acts, among other functions, as a vasodilator (173). PGE2 levels increase in kidney after an ischemia-reperfusion injury (171). The inhibition of its degradation and the activation of its synthesis attenuated kidney damage and preserved renal function after ischemic-induced AKI indicating the importance of this lipid mediator in renal physiology (174, 175). In addition, COX-2 and PGE2 mediated the beneficial effect of administration of mesenchymal stem cells pretreated with IL-17A, which was shown to preserve renal function and reduce kidney damage following ischemic-induced AKI (176). Although the increased signaling of E prostanoid (EP) receptor type 4 was linked with better outcomes after ischemic-induced AKI, EP3 receptor antagonism and deficiency also seemed to be beneficial (171, 175, 177). In fact, it reduced inflammation and neutrophil recruitment as well as necroptosis (171).

Ischemic-induced AKI is accompanied by the increased activity of leukotriene A4 (LTA4) hydrolase, the enzyme responsible for LTB4 synthesis (178). Although LTB4 levels remain poorly characterized in the kidney following ischemic injury, the upregulation of its biosynthetic enzyme suggests a role in promoting neutrophil recruitment and monocyte differentiation within the injured renal tissue. Some CYP450 metabolites have also been described to be either beneficial or detrimental following an ischemic injury. For instance, reducing EET catabolism might improve AKI outcomes, but in a recent study, it led to increased levels of the AA metabolite 20-HETE, which is considered detrimental in ischemic-induced AKI causing vasoconstriction, and more severe renal inflammation and tissue damage (179). Nonetheless, the role of 20-HETE in AKI remains debated following an ischemic insult, as evidenced by its aggravating effects in bilateral, but not unilateral, ischemia-reperfusion-induced AKI. These conflicting findings highlight the context-dependent nature of 20-HETE involvement and the need for further investigation (180–182).

From a dietary perspective, omega-3 (n3)-PUFAs are increasingly recognized for their role in improving overall health, in reducing the risk of chronic diseases, and for the potential pro-resolving effect of their oxidized metabolites. Their supplementation in diet has been proposed to reduce the risk of AKI after an ischemic injury. However, in male mice, although this supplementation increased systemic and renal levels of n3-PUFAs, it did not attenuate renal damage, inflammation, and neutrophil recruitment (183).

In summary, lipid mediators that increase renal perfusion appear to promote kidney health and confer protection against ischemic-induced AKI. Altogether, these findings establish a foundation for future studies on the role of lipids in AKI following an ischemic injury and their potential therapeutic applications, while highlighting the need for further investigation to fully elucidate their mechanisms and clinical relevance.

RENAL EPITHELIAL CELLS AND PATHOGEN-INDUCED INFLAMMATION

The renal medullary CD is the first kidney segment encountered by ascending UPEC (184). Growing evidence suggest a clear role for ICs in fighting UTIs (110, 185). Ascending UPEC preferentially attaches to the apical surface of ICs, triggering potent inflammatory responses (186). UPEC use its FimH adhesive protein to bind to the apical mannosylated desmoglein 2 (DSG2) receptor located in the apical membrane of CD cells (187). LPS on the outer membrane of UPEC is recognized by Toll-like receptor 4 (TLR-4) located on the apical membrane of ICs (186) (Fig. 5). Chassin et al. (186) demonstrated that CD cells play a crucial role in clearing bacteria from the kidney, via both a TLR4-mediated, and a myeloid differentiation primary response 88 (MyD88)-dependent pathways, activating NF-κB, ERK1/2, p38, and JNK, and TLR4-independent pathways, involving TNF-mediated activation of TRAF2, ASK1, and JNK leading to the secretion of MIP-2 and recruitment of immune cells. UPEC exposure to isolated human and mouse ICs upregulates mitogen-activated protein kinase kinase kinase 7, which is a critical component of the NF-κB signaling pathway. This activation triggers the release of inflammatory cytokines like IL-1, IL-6, and TNF-α (188, 189).

A previous study identified six IC subtypes including one hybrid principal cell (PC)-IC subtype in the human kidney by single-cell RNA sequencing (185). Upon UPEC exposure hybrid PC-ICs exhibited plasticity, shifting their RNA velocity from PCs to type A ICs (A-ICs). Phagosome maturation emerged as a critical pathway in A-ICs, driven by the proton-pumping V-ATPase located on their apical membrane. The authors used a murine UTI model to show increased expression of the B1 subunit of the V-ATPase (Atp6v1b1) 1 h following transurethral UPEC injection, suggesting that V-ATPase-expressing epithelial cells may act as bacterial phagocytes.

ICs are the primary producers of antimicrobial peptides (AMPs) in the kidney, highlighting their critical role in innate immunity (190). AMPs primarily kill pathogens by disrupting bacterial membranes but also disrupt microbial processes, and modulate host immune responses (191). IC ribonucleases (RNases) are a class of AMPs (190). RNase 7 is upregulated during infection and helps reduce bacterial burdens in UTI (192). Lower levels of RNase 7 are associated with UTI history. RNase 4, also expressed by ICs, increases in response to UPEC exposure and is lower in females with a history of UTI (184, 193). Defensins form another group of AMPs (194). β-defensins, such as Defb1, are upregulated in both PCs and ICs during UPEC infection (184). α-defensins, including human neutrophil peptides 1–3 (HNP1-3) and human α-defensin 5 (HD5), also play critical roles in combatting pathogens, with HD5 expression increasing during UTIs (195, 196). LL-37, the cathelicidin encoded by CAMP gene in human, is produced by ICs and increases during UTI (197). LL-37 also works synergistically with other AMPs, particularly the HNP1-3 (α-defensins), enhancing bacterial killing while reducing host cytotoxicity (196). Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is secreted from ICs into the urine and sequesters iron from bacteria (198). Adrenomedullin (ADM) is another AMP highly expressed by ICs, as confirmed by RNA sequencing and single-cell transcriptomics in both murine and human kidney cells (185, 199). It plays a dual role in immune responses, exhibiting antimicrobial activity against E. coli, and enhancing inflammation by increasing IL-6 expression through NF-κB signaling (200, 201).

Limited studies have explored lipids and their metabolism in sepsis-induced and endotoxemia-induced AKI. As in ischemic-induced AKI, increased prostacyclin levels seemed to alleviate AKI induced by LPS (202). Another study explored the involvement of TXA2, a well-documented vasoactive prostanoid also known to reduce the glomerular filtration rate, in the context of LPS-induced AKI (203). The authors showed that COX-1 was responsible for its synthesis and that inhibiting this enzyme was partially beneficial, as shown by modestly improved renal function, higher glomerular filtration rate, but unchanged levels of IL-1β and TNF-α.

In addition, the role of the monounsaturated fatty acid oleic acid (OA; 1 n-9) was recently assessed in LPS-induced AKI (204). OA-treated mice showed improved renal function, decreased serum levels of proinflammatory cytokines (INF-γ, TNF-α, and IL-2) and increased serum levels of the anti-inflammatory cytokine IL-10 compared with untreated mice. Although the need for further studies remains, this finding highlights the potential benefits of fatty acids, readily available through dietary intake or supplementation, in improving AKI outcomes.

Finally, alterations in oxidized lipids—arising from LOX, COX, and CYP450 enzymatic activity as well as nonenzymatic oxidation—were observed in the plasma of patients with sepsis-associated AKI (205). These findings underscore the growing importance of understanding lipid metabolism and its role in the prevention, assessment, and treatment of AKI.

CONSEQUENCES OF RENAL INFLAMMATION

Renal inflammation can result in serious outcomes, primarily presenting as AKI and CKD (135). AKI is associated with high mortality rates, particularly in hospitalized patients. Even after recovery, AKI raises the likelihood of future kidney issues and the progression to CKD. CKD is characterized by kidney damage or reduced function lasting for 3 mo or more, potentially advancing to end-stage kidney disease that necessitates dialysis or a transplant (135, 206). CKD is linked to many severe complications, such as a higher risk of cardiovascular disease, hyperlipidemia, anemia, and metabolic bone disorders (207). Renal inflammation can extend beyond the kidneys, triggering the release of inflammatory mediators into the bloodstream, which can result in dysfunction in distant organs (208). This inflammatory condition contributes to insulin resistance, oxidative stress, and impairment of endothelial function. Understanding the mechanisms connecting inflammation to these outcomes is critical for developing targeted interventions.

Despite significant advances in understanding renal inflammation, current therapeutic approaches remain limited (209). Although traditional treatments mainly aim to manage symptoms and slow disease progression, there are no targeted therapies that directly address the early onset of inflammation associated with AKI (209). Current management of kidney disease includes supportive care, the removal of nephrotoxic medication, and treating the underlying conditions that contribute to kidney fibrosis (210). Ongoing research is exploring the use of pharmaceutical agents to mitigate renal parenchymal damage, targeting inflammatory processes of renal fibrogenic cells in CKD patients (209, 210). In parallel, agents like the mineralocorticoid receptor antagonist finerenone, the anti-IL-1β antibody canakinumab, and the nonspecific phosphodiesterase inhibitor pentoxifylline are being studied for their ability to target chronic inflammation and fibrotic pathways associated with CKD (209, 211). However, these potential treatments are still in the experimental phase and have not yet been applied in clinical practice (209, 212).

Finally, targeting lipid metabolism and signaling to improve AKI outcomes should be more thoroughly characterized. Their modulation by existing therapeutics showed some undesirable renal effects. Long-term pharmacological inhibition (e.g., by NSAIDs) of the prostaglandin synthesis has been associated with reduced renal blood flow, leading to acute and, in some cases, chronic renal failure (173, 213–215). Nevertheless, due to their role in the initiation of early inflammation, the therapeutic potential of modulating specific lipid pathways remains both promising and worthy of continued exploration.

CONCLUSIONS

Understanding the molecular and cellular mechanisms of acute inflammation provides crucial insights into the body’s immune responses to injury and infection. By focusing on the kidney, a key organ frequently impacted by inflammatory processes, we highlight the complex interplay of immune and nonimmune cells in inflammation. This knowledge offers valuable perspectives for developing targeted therapeutic strategies to manage both systemic and kidney-specific inflammatory diseases, ultimately improving patient outcomes in conditions such as AKI, UTI, and CKD.