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Scholze, A. Inflammasome Components in Kidney Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/19984 (accessed on 11 December 2025).
Scholze A. Inflammasome Components in Kidney Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/19984. Accessed December 11, 2025.
Scholze, Alexandra. "Inflammasome Components in Kidney Disease" Encyclopedia, https://encyclopedia.pub/entry/19984 (accessed December 11, 2025).
Scholze, A. (2022, February 28). Inflammasome Components in Kidney Disease. In Encyclopedia. https://encyclopedia.pub/entry/19984
Scholze, Alexandra. "Inflammasome Components in Kidney Disease." Encyclopedia. Web. 28 February, 2022.
Inflammasome Components in Kidney Disease
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This entry is adapted from the peer-reviewed paper 10.3390/antiox11020246

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. Clinical research on inflammasome components points at the importance of patient comorbidities, kidney disease stage, and treatments as important drivers of inflammasome component alterations.

acute kidney injury chronic kidney disease inflammasome redox signalling interleukin-18 NLRP3 AIM2 kidney transplant caspase-8 NLRC4 NLRP6.

1. Introduction to Kidney Disease and Inflammation in Kidney Disease

The 2020 analysis of the Global Burden of Disease Study 1990–2017 estimated the global prevalence of chronic kidney disease (CKD) to be 9.1%, corresponding to 697.5 million cases [1][2]. The all-age global prevalence of CKD increased by 29.3% during this period due to aging of the population globally. The number of deaths at all ages attributable to CKD increased by 41.5%. While age-standardized CKD mortality did not change between 1990 and 2017, it declined by 41.3% for chronic obstructive pulmonary disease, 30.4% for cardiovascular disease, and 14.9% for cancer [1][2]. Therefore, new strategies for early detection and prevention of CKD and the development of more effective therapies are needed.
CKD can result from kidney injuries of any cause if the process of injury was of sufficient duration and/or intensity. It is defined by the presence of decreased kidney function or kidney damage for more than three months, while acute kidney injury (AKI) comprises multiple renal conditions associated with a sudden decrease in kidney function. Kidney disease refers to a heterogeneous group of disorders that impact on the function or structure of the kidney. It is important to note that even milder reductions in kidney function are associated with an increased risk for AKI, complications in other organ systems than the kidneys, and mortality [3].
Inflammatory and immunological processes are intimately linked to kidney disease. They contribute to the initiation of injury in AKI, for example during sepsis, but also play an important role for AKI’s extension and maintenance phase [4], and AKI-to-CKD transition [5]. In addition, inflammatory and immunological processes are involved in a wide range of CKD causes, like diabetes mellitus or systemic lupus erythematosus. Importantly, they also contribute to CKD progression, independent of the underlying cause [6]. Finally, CKD-related morbidity, such as CKD-attributable cardiovascular disease (CVD), and CKD mortality are related to chronic inflammation [7].
Inflammasomes and inflammasome components have an important role in infectious and non-infectious tissue injury [8]. Herein discusses the involvement of inflammasome components in the pathophysiology and course of kidney diseases. Excellent publications have been published on the topic, reporting inflammasome taxonomy and tissue expression pattern, molecular mechanisms of inflammasome activation and function, respective renal disease models, roles in human kidney disease, inflammasome gene mutations and polymorphisms, and inflammasome-related therapeutic options, such as the Refs. [9][10][11].

2. Inflammasome Components in AKI

2.1. Preclinical Data on Inflammasome Components in AKI

AKI is associated with a high incidence of cell death and the production of cellular debris. The most prominent cause of acute renal damage is acute tubular necrosis (ATN). ATN is linked to an inflammatory response comprising monocytes/macrophages and neutrophil infiltration, which exacerbates the kidney damage [12][13]. The evidence for the inflammasome’s function in acute renal disease is compelling. Deficiency of the inflammasome component, caspase-1, in animals provides resistance against AKI in several models such as cisplatin and ischemia-induced acute renal failure [14][15][16][17]. Moreover, inhibition of nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) by hydroxychloroquine decreased NF-κB signalling, as well as cathepsin-B and L activities, and protected rodents from AKI [18]. The extracellular matrix (ECM) components biglycan and hyaluronan, as well as ATP acting via P2X7 receptors, activated the NLRP3 inflammasome [19][20]. The pathogenic roles of the NLRP3 inflammasome have been demonstrated in ischemia-reperfusion injury (IRI) [18][21][22][23], folic acid-induced AKI [24], rhabdomyolysis-induced kidney injury [25], and contrast-induced kidney injury [26]. During contrast-induced AKI, canonical NLRP3 inflammasome activation in local and migratory macrophages led to elevated IL-1β levels in mice, whereas Nlrp3-/- animals were protected [26]. Infection-induced AKI models have also been shown to activate canonical inflammasomes. In a caecal ligation puncture model (sepsis-induced AKI), NLRP3 deficiency and caspase-1 suppression reduced kidney injury, inflammation, and caspase-1 activation [27]. Furthermore, mice with caspase-1 deficiency were protected from endotoxemic AKI, hypotension, and mortality caused by LPS [28]. Neutralization of IL-1β and IL-18, on the other hand, was unable to reverse LPS-induced AKI, implying that the non-canonical inflammasome and pyroptosis play an important role [29]. Accordingly, the induction of pyroptosis has been related to caspase 11 upregulation, the non-canonical pyroptosis pathway, demonstrated in renal proximal tubular cells treated with LPS. The authors suggest that pyroptosis induction could be an early event in septic models [30]. Furthermore, Astragaloside-IV protected from cisplatin-induced AKI by promoting autophagy and inhibiting NF-kB signalling, thus lowering the expression of inflammasome components [31]. Interestingly, NLRP1 activation was elevated in cisplatin-induced AKI, likely upstream of caspase-1 activation [32]. In this model, the deletion of caspase 11 promotes the downregulation of IL-18 urine secretion, decreasing tubular damage, immune macrophage, and neutrophil infiltration, and attenuating renal dysfunction. On the other way, caspase 11 upregulation induces the cleavage of gasdermin D into gasdemin N to trigger pyroptosis [33]. In addition, the deletion of GASMDE, a member of the GASDM family, decreases cisplatin-induced damage by blocking pyroptosis and IL-1β release [34]. During the pathogenesis of uric acid-induced nephropathy, uric acid crystals activate the NLRP3 inflammasome, suggesting a novel pathomechanism of crystalline nephropathy [35]. The NLRP3 inflammasome complex must be activated for renal IL-17A to be produced, which is an essential proinflammatory cytokine in AKI [36]. The discovery of the underlying mechanisms could assist the therapeutic suppression of IL-17A in AKI. Further, Deplano et al. reported that P2X7R (P2X purinoceptor) deficiency in rats reduced the activation of NLRP3-inflammasome in macrophages, and also crescentic glomerular damage in experimental nephrotoxic nephritis coupled with crescentic glomerulonephritis [37]. Together, these data suggest that inflammasome components are promising therapeutic targets for treatment of AKI.
Several of the signalling molecules involved in regulating programmed cell death also modulate inflammasome activation in a cell-intrinsic manner. Necroptosis is typically seen as a back-up that kicks in when apoptosis is prevented; pyroptosis is a fundamental cellular mechanism triggered by the inflammasome in response to a wide spectrum of Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) [38]. Activation of inflammatory caspases such as caspase-1, caspase-4, caspase-5, and caspase-11 leads to pyroptosis, which relies on gasdermin-D to produce plasma membrane pores [39]. Due to their limited potential to release IL-1β, the prevalence of pyroptosis in tubular epithelial cells (TECs) has been disputed [40]. Pyroptosis, characterised by elevated caspase-1 activation and IL-1β production, has been proposed to emerge in kidney tubular cells during renal IRI [41].
Mice lacking distinct inflammasome components were utilised to establish the inflammasome’s participation in several experimental models of renal damage, but the specific role of intrinsic renal cells in inflammasome activation remains unknown [42]. Some studies stated that TEC apoptosis and pyroptosis are the key drivers of contrast-induced AKI [43][44], others did not show TEC apoptosis [26][45], canonical inflammasome formation in TECs, or IL-1β release from TECs in response to contrast-induced AKI [26][46]. Necroptosis mediated NLRP3 inflammasome plays a key role in the pathogenesis of lupus nephritis [47] as well as the transition from AKI to CKD [48]. Emerging evidence indicates that several signalling mechanisms that had been assumed to be biochemically independent for a long time communicate with one another. Nevertheless, the impact of apoptotic and regulated necrosis signalling molecules on the inflammasome is inconsistent and depends on the cell type and cellular environment. As a result, it is still a long way from understanding how these chemicals lead to altered inflammasome expression across various settings, as well as why these cell death mechanisms have developed to participate in inflammasome activation.

3. Inflammasome Components in CKD

3.1. Preclinical Data on Inflammasome Components in CKD

The NLRP3 inflammasome also contributes to the pathogenesis of CKD. In murine unilateral ureteric obstruction (UUO), IL-18 neutralization reduces kidney damage and fibrosis [49]. Additional biological factors, such as the ECM components biglycan and hyaluronan, stimulate NLRP3 inflammasome activation, thus aggravating CKD progression [50]. Biglycan-deficient animals are resistant to damage following UUO [19]. Additionally, NLRP3-deficient mice have less tubular damage and decreased renal inflammation when compared to wild-type controls upon UUO [51][52][53]. The NLRP3 inflammasome was implicated in the pathogenesis of multiple kidney diseases, such as adenine-induced tubulointerstitial nephritis [54], metabolic syndrome-associated nephropathy [55][56], hyperhomocysteinemia-induced glomerulosclerosis, proteinuria-induced tubular injury [57], angiotensin II-induced hypertensive kidney injury [58], and diabetic kidney disease (DKD) [59]. These studies demonstrated the pathological roles of NLRP3 in both inflammasome-dependent and inflammasome-independent manners during CKD. Lack of NLRP3 inflammasome and related genes results in lower kidney damage, cell death, inflammation, and fibrosis. Nevertheless, there are also still unresolved questions. For example, in UUO, blocking the renin-angiotensin system decreased NLRP3 inflammasome and boosted water channel AQP2 activity [60].
In DKD, both immune and non-immune cells of the glomerulus released IL-1β and IL-18, which exacerbated diabetic nephropathy (DN) [61]. Additionally, renal podocytes and endothelial cells have higher expression of NLRP3 and caspase-1, suggesting its involvement in the pathogenesis of DKD [59]. Moreover, genetic and pharmacological suppression of the NLRP3-inflammasome together with IL-1β protected mice from DKD [59][61]. Several studies also showed that allopurinol, quercetin, and saxagliptin, through reducing the NLRP3/ASC inflammasome, protected mice from DN [62][61][63][64]. Yuan et al. discovered that a lack of acid ceramidase (AC) boosted the stimulation of the NLRP3-inflammasome and the secretion of exosomes, which in turn boosted the production of IL-1β in diabetic mice [65]. Dihydroquercetin effectively protects against DN by reducing reactive oxygen species (ROS)-induced NLRP3-inflammasome activation [66]. Shahzad et al. conducted bone marrow transplant studies with control, Nlrp3-/-, and caspase1-/- mice and discovered that the NLRP3 inflammasome in native renal cells plays a substantial role in the evolution of DKD [59]. Notably, it is yet unknown if active caspase-1 causes pyroptosis in podocytes during DKD. Furthermore, the NLRP3 inflammasome is known to be expressed by tubular epithelial cells in the kidney [67]. As a result, the role of NLRP3 in tubules in the progression of renal interstitial fibrosis in DKD remains unknown and deserves additional investigations. The expression of the NLRP3-inflammasome in the kidney has been linked to salt-sensitive hypertension [68][69]. MCC950, an NLRP3 antagonist, lowered blood pressure and fibrosis, reduced renal inflammation, and protected against kidney failure [70]. Kidney inflammation caused by the NLRP3 inflammasome has also been linked to the advancement of Immunoglobulin A (IgA) nephropathy. In mice, both genetic deficit and pharmacological suppression of NLRP3 employing shRNA in a preventive or therapeutic way significantly slowed the development of IgA nephropathy [71]. IL-1β receptor inhibitors additionally stopped the course of pre-existing IgA nephropathy in mice [72]. These findings imply that targeting NLRP3-inflammasome can be a promising therapeutic strategy for IgA nephropathy. It is still unclear whether NLRP3′s inflammasome-independent actions are involved in the pathogenesis of IgA nephropathy.
Besides, ASC-deficient mice were protected from hypertensive nephrosclerosis [73], and mice lacking NLRP3 were protected from hyperhomocysteinemia-induced glomerulopathy [74] and Western diet-induced nephropathy [56]. Together, inflammasome components play a crucial role in various forms of CKD, and are therefore putative therapeutic targets for CKD.

4. Summary and Perspectives

In summary, herein demonstrated the considerable diversity of the inflammasome components and their interactions with various molecular partners involved in kidney disease pathophysiology.

In preclinical AKI models, canonical and non-canonical NLRP3 effects have consistently been reported, but NLRP1 could be involved, too. Reactive oxygen species contribute to inflammasome priming and activation, while mitochondria and ER stress both contribute to the activation of NLRP3 inflammasomes. Involvement of inflammasome components in AKI has been described in monocytes-macrophages, but also in renal epithelial cells. Furthermore, crosstalk between inflammasome components and cell death pathways involving caspase-8 was reported, both in leukocytes and epithelial cells in AKI models. Clinical data are consistent with an involvement of inflammasome components in AKI, but data are still sparse. In line with the systemic nature of AKI and the organ-crosstalk involved, alterations of IL-1β and IL-18, but also effects on NLRP3 concentrations have been reported in blood serum. A protective role for NLRP6 was suggested in acute tubular injury, while NLRC4, NLRP3, and AIM2 were involved in acute loss of kidney function in transplanted kidneys. Urinary IL-18 concentrations have been under intense investigation as a biomarker in AKI. Herein identified the importance of the temporal pattern of IL-18 concentration changes that could be helpful to determine the optimal timing of inflammasome-targeting therapies in AKI.
In preclinical CKD models, involvement of NLRP3 and inflammasome substrates IL-1β and IL-18 have been reported for CKD pathogenesis. Alterations of inflammasome components were localized to immune cells, resident glomerular cells, and endothelial cells. Furthermore, a multitude of mechanisms related to redox signalling, mitochondria and ER stress are known, that contribute to NLRP3 priming and activation. Clinical data clearly point to an involvement of inflammasome components in CKD; related to CKD causes, but also CKD progression and CKD-induced morbidities, like CVD. Besides the sensory component NLRP3, alterations for AIM2, NLRC4 and NLRC5 were also reported. As several of the causes underlying CKD are of systemic nature, as in diabetes mellitus or Systemic lupus erythematosus (SLE), and since advanced CKD affects the entire body, alterations of inflammasome components and substrates in CKD are not only found in renal tissue, but also in circulating and infiltrating immune cells, in whole blood, and blood plasma.
Finally, it identified differential regulation of inflammasome components that require consideration in research on the pathogenesis of human CKD. First, frequent comorbidities as hypertension and metabolic syndrome, but also treatments, exert effects on inflammasome components; hence, control groups should be matched accordingly. Second, reduction of PBMC NLRP3 or unexpected low amounts of NLRP3 or caspase-1 were observed in some patient populations with Lupus Nephritis (LN), urate nephropathy (UAN), and End-Stage Kidney Disease (ESKD).  This could result from increased concentrations of uremic toxins, as shown for high indoxyl sulfate concentrations, or represent a negative feedback regulation of inflammasome components in circulating immune cells that needs further study.

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