The immune system is composed of two arms, the innate and adaptive immunity, that are responsible for both immediate and long-term immunity to pathogen- and non-pathogen-derived antigens. Innate immunity detects infections, changes in cellular homeostasis and tissue damage, subsequently generating inflammation, tissue repair and homeostatic balance restoration ^[1]. These effects are promoted by the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs and DAMPs bind to pattern recognition receptors, which include Toll-like receptors (TLRs), cytoplasmic NOD-like receptors (NLRs) and absent in melanoma 2-like receptors (AIM2) ^[2]. Previous studies have demonstrated the role of several members of the NLR family in the formation of inflammasomes, multiprotein complexes capable of recognizing inflammation-inducing stimuli. These complexes activate pro-caspase-1, which is responsible for the cleavage of multiple substrates, mainly the proinflammatory cytokines IL-1β and IL-18 ^[3]. The release of these cytokines by the inflammasome can also be carried out through an inflammatory form of programmed cell death named pyroptosis ^[4]. Therefore, the activation of the inflammasome develops innate immunity activity in response to tissue infection. Noninfectious stimulus can also activate the inflammasome ^[5].

2. NLR Family Inflammasomes

The NLR family comprises 23 human genes. Members of this family show common structural elements: C-terminal series of leucine-rich repeats (LRRs) and central nucleotide binding domains (NBD), a component of the larger NACHT domain ^[6][7]. Furthermore, NLR family members can be divided into different subfamilies depending on their N-terminal effector domain: caspase-activation and recruitment domain (CARD), baculovirus inhibitor of apoptosis protein repeat (BIR) or pyrin domain (PYD). The NLRP and NLRC subfamilies are the most important, the former being the best-characterized subfamily of NLRs. The NLRP subfamily members have PYD domains at their N-terminal while the NLRC proteins have one or more CARD domains ^[7][8][9]. NLR family members NLRP1, NLRP3 and NLRC4 have been the best studied in inflammasome formation ^[10].

2.1. NLRP Subfamily

The NLRP subfamily is composed of 14 members in human genome, plus 3 paralogs in mouse being NLRP1 (NALP1/CARD7) the first to be described in forming inflammasomes ^[11]. Its structure consists of a N-terminal PYD followed by a NACHT domain and LRRs. This is also contributed by a C-terminal extension containing a function-to-find domain (FIIND), which auto processes NLRP1 into two polypeptide chains, and a CARD domain, that leads to caspase-1 activation and the consequent proinflammatory cytokine release ^[12][13]. It has been reported that NLRP1 mutations can play a role in inflammatory diseases such as psoriasis ^[14], rheumatoid arthritis (RA) ^[15] or in systemic lupus erythematosus (SLE) ^[16]. NLRP3 inflammasome (Cryopyrin/Nalp3/Cias1/Pypaf1) is the most widely studied and is the only known member to be activated by numerous pathogenic and sterile inflammatory signals. Furthermore, NLRP3 plays a role in the regulation of IL-1β production in macrophages ^[17][18]. NLRP3 is composed of the NLRP3 scaffold, an adaptor apoptosis speck-like protein (ASC) and the effector procaspase-1. It interacts with ASC via PYD-PYD homotypic interactions to promote the formation of the inflammasome by recruiting and activating procaspase-1 to generate active caspase-1 (Figure 1b).

2.2. IPAF-NAIP Subfamily

Its most well-studied element, NLRC4 (IPAF/CARD12), was previously characterized as an ICE-protease activating factor (IPAF) regarding its capacity for activating caspase-1. Nevertheless, posterior studies clearly placed its domain structure in the NLR family, and as it possessed a CARD domain, it was renamed NLRC4 ^[19]. The CARD domain allows it to directly bind to the CARD of caspase-1 without the participation of ASC ^[20]. However, NLRC4 is able to bind to ASC and efficiently activate caspase-1, as well as caspase-8, an apoptotic caspase ^[21]. NLRC5 is a less well-known inflammasome that links both innate and adaptive immune responses by regulating major histocompatibility complex (MHC) I class expression ^[22]. It is expressed in macrophages, dendritic cells, T cells, B cells and fibroblasts ^[23].

3. Non-NLR Family Inflammasomes

Recently, other inflammasomes not belonging to the NLR family have been widely described, such as the proteins absent in melanoma 2 (AIM2) and pyrin inflammasomes. AIM2 was described as a sensor able to trigger inflammasome activation, pyroptosis and release of IL-1β and IL-18 in response to intracellularly delivered double-stranded DNA (dsDNA) detection ^[24]. AIM2 is a member of the ALR family of proteins, composed of an N-terminal PYD domain and a C-terminal HIN (hematopoietic, interferon-inducible and nuclear localization) domain ^[25]. Moreover, it negatively regulates inflammation and type I interferon (IFN) responses independent of its inflammasome function ^[26]. Different studies have elucidated a link between increased AIM2 expression and several human diseases, such as atherosclerosis, skin disease or chronic kidney disease ^[27].

4. Mechanisms of NLRP3 Inflammasome Activation

The inflammasome can be understood as a two-sides element and it regulates pathogen infection, but when the immune response triggered is not tightly regulated, it can be involved in pathologies such as CAPS and autoinflammatory disorders ^[28]. Inflammasomes can recognize a wide variety of endogenous or exogenous, sterile or infectious stimuli within the cell (PAMPs and DAMPs), which trigger its assembly and activation. This process can be explained by considering the upstream sensors recognizing activating signals, the adapters and the downstream effectors ^[29]. The unfeasibility of a direct interaction between NLRP3 and this diversity of stimuli led to a cellular event producing a conformational change in NLRP3, converting it into an active form. Nevertheless, there is no unique mechanism for the activation of the NLRP3 inflammasome ^[30]. NLRP3 activation can be triggered by PAMPs and DAMPs detection via PRRs, such as TLRs and NLRs, by cytokine stimulation via IL-1 receptor (IL-1R) or through TNF link to tumor necrosis factor (TNF) receptors TNFR1 and TNFR2 ^[31]. Moreover, there are mediators that facilitate signal transduction of these receptors: the adaptor protein myeloid differentiation primary response 88 (MyD88), the apoptosis signal-regulating kinase (ASK)1 and ASK2, interleukin 1 receptor-associated kinase (IRAK)1 and IRAK4, caspase-8 (CASP8), Fas-associated protein with death domain (FADD), ubiquitin-binding protein SHARPIN and TRAF-interacting protein with forkhead-associated domain (TIFA). All these elements trigger the transcription of NF-κB, which promotes the transcription of NLRP3 and IL1B genes, habilitating the cell for responding to NLRP3 activators ^[32]. NLRP3 inflammasome activation in macrophages is a two-step process, thus it requires a priming signal. In the priming process, a non-activating stimulus causes the transcriptional expression of the main components of the inflammasome, this being the ‘first hit’. A second stimuli or ‘second hit’ aggravates the functional activity of the NLRP3 inflammasome ^[33]. Activation of the NLRP3 inflammasome can be produced by different stimuli, including ionic flux, K+ efflux, Ca2+ influx, Na+ influx and Cl- efflux, reactive oxygen species (ROS) and mitochondrial dysfunction or lysosomal damage. K+ efflux channels P2X purinoceptor 7 (P2X7R) participate in this type of inflammasome activation. Other plasma-membrane-resident Ca2+ channels, namely transient receptor potential melastatin 2 (TRPM2), TRPM7 and transient receptor potential vanilloid 2 (TRPV2), can lead to Ca2+ influx to the cytosol ^[28] (Figure 1c). NLRP3 inflammasome can be regulated in a post-transcriptional and post-translational level. At the post-transcriptional level, epigenetic factors such as DNA methylation and histone acetylation can regulate NLRP3 mRNA expression in response to Mycobacterium tuberculosis infection ^[34]. Dysregulation of epigenetic mechanisms could contribute to the pathological development of autoinflammatory syndromes by upregulating the expression of inflammasome components. MicroRNAs are also studied as post-transcriptional regulators of NLRP3 inflammasomes (miR-223, miR-133a, miR-7, miR-30e…) ^[29][35].

5. Inflammasome Effector Functions

As previously stated, inflammasomes play a crucial role in the innate immune system by their ability to control the activation of the proteolytic enzyme caspase-1, which leads to proteolytic maturation of the proinflammatory cytokines IL-1β and IL-18, as well as pyroptosis cell death ^[36]. Mature IL-1β binds to IL-1R, promoting the heterodimerization of the receptor and the subsequent recruitment of components such as MyD88 ^[37]. IL-1β leads the release of other cytokines such as IL-1α, IL-6 and TNF-α as well as other factors that control growth and differentiation of immune cells ^[38]. IL-18 participates in many physiological pathways. A higher level of IL-18 can cause metabolic syndromes. For instance, chronic inflammation generated in adipose tissues can lead to insulin resistance and type 2 diabetes mellitus ^[39]. Another important process carried out by inflammasomes is a lytic form of programmed cell death named pyroptosis. Both canonical inflammasome signaling, recruiting caspase-1, and noncanonical inflammasome, via caspase-4, caspase-5 (in humans) and caspase-11 (in mice), can trigger pyroptosis. It is characterized by cell swelling, membrane lysis, and release of inflammatory compounds into the extracellular space, such as IL-1β, IL-6 and IL-18. Whereas the effector functions have been widely studied, there are several additional roles of the inflammasome complexes that have been less characterized. IL-1β is a leaderless cytoplasmic protein whose secretion mechanisms are poorly defined. An endoplasmic reticulum (ER)/Golgi-independent mechanism termed ‘unconventional protein secretion’ was shown, and it was dependent on caspase-1 activation. However, the specific mechanisms and molecular components involved in this process are unclear. Another emerging role of inflammasomes is the activation of eicosanoids, bioactive molecules derived from membrane lipids that play a role in homeostatic and pathological processes. Furthermore, a link between inflammasome activation and autophagy as well as regulation of phagosome maturation have been observed ^[40].

6. The Role of the Inflammasome in Adaptive Immunity and Autoimmunity

The production of proinflammatory cytokines is critical for an effective innate response, as well as a mechanism by which the innate immune system influences the subsequent development of an adaptive immune response ^[41]. As it is well known, inflammasomes are components of the innate immune system that produce the proinflammatory cytokines IL-1β and IL-18, and they drive the differentiation of specific lineages of helper T cells (Th1, Th2, Th17 and regulatory T cells), which are the main players in adaptive immunity ^[42]. On the other side, an aberrant inflammasome activation is responsible for the development of CAPS, as well as other common diseases such as metabolic disorders, crystal-related diseases and autoimmune diseases. Inflammation is also crucial in many renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). Although the innate immune system is always involved, in these conditions, the adaptive immunity plays the main role ^[43]. Concerning autoimmune diseases, they are characterized by self-reactive cells and the overproduction of autoantibodies, produced because of a lack of immunological tolerance and aberrant autoreactive immune responses. The pathogenesis of autoimmune diseases remains to be clarified, but it has been demonstrated that aberration in innate and adaptive immunity is involved. NLRP3 inflammasome has been recently linked with innate immune signal recognition and induction of autoreactive immune responses, probably being a checkpoint in innate immunity to cause distorted adaptive immunity ^[44][45]. Indeed, multiple polymorphisms in inflammasome genes have been associated with the susceptibility and development of autoimmune diseases. For instance, rare gain-of-function variants can be implicated in hereditary inflammatory diseases, characterized by uncontrolled production of IL-1β and/or IL-18, named inflammasomopathies. Mutations in NLRP3 are the prototypic inflammasomopathy, but they have also been described as autoinflammatory diseases associated with mutations that activate the NLRP1, NLRC4 and pyrin inflammasomes ^[46][47]. Moreover, single nucleotide polymorphisms (SNPs) play a crucial role in autoimmune diseases, and they can affect the priming of inflammasomes, some of their components or end products (IL-1β, IL-18) ^[48].

7. Inflammasome Involvement in Autoimmune Kidney Diseases

7.1. Lupus Nephritis

SLE is a chronic disease that frequently affects the kidney. Lupus nephritis (LN) is the most common renal disease, involving approximately 50% of patients with SLE. This autoimmune disease mostly affects women of the reproductive age. In men, the disorder could be more aggressive. Patients usually have LN at an early age, and it usually presents itself in the initial stages of the disease. Patients with this renal impairment have an increased mortality rate. In total, 10–30% of patients with LN progress to renal failure requiring kidney replacement therapy ^[49][50]. Irregularities in innate and adaptive immunity contribute to the pathogenesis of SLE. LN occurs when the transcription of genes associated with neutrophils increases. The rise in IFN precedes the activation of neutrophils. The increment of IFN causes the differentiation of B cells into plasmablasts and produces inflammation of specific tissues through neutrophils and active myeloid cells. When these neutrophils die, extracellular neutrophil traps (NETs) appear ^[49]. NETs are meshing-chromatin fibers combined with granules derived from antimicrobial peptides and enzymes that play an important defense role ^[51]. These meshes help to maintain antigen-specific autoantibody production ^[49]. The formation of immune complexes that are deposited in the glomerulus is derived from the production of antibodies against nuclear and cellular antigens. Immune complexes can activate complement and cause kidney damage, especially through the alternative pathway. Plasma interstitial cells generated by B and T cells aggregate in the renal tubulointerstitium also generating the production of autoantibodies ^[50]. An increase in the inflammasome’s components was observed in biopsies of patients with LN as PYCARD (ASC), caspase-1 and IL-18, indicating their contribution to the disease ^[52]. Furthermore, the increased transcription of IL-18 in the tubulointerstitial and glomerular compartments ^[52] correlates with the severity of LN and the onset of proteinuria ^[53].

7.2. ANCA Glomerulonephritis

ANCA associated with vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. AAV affects small and medium vessels, especially organs such as the kidney and lung. Pauci-immune and necrotizing glomerulonephritis are frequently associated in patients with vasculitis being more prevalent in men over 50 years of age. ANCA vasculitis is usually associated with ANCA-myeloperoxidase (MPO), ANCA-proteinase 3 (PR3) or ANCA-negative serotype positivity. This pathology is classified into different clinical variants such as microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) or vasculitis limited to renal tissue ^[54]. Both innate and adaptive immunity participate in the development of AAV, although the exact mechanisms remain to be elucidated ^[54]. Neutrophils play a fundamental role in the pathogenesis of AAV inflicting tissue damage after degranulation induced by ANCA antibodies. Apart from antibodies, T cells are also involved in disease pathogenesis. Neutrophils secrete cytokines that recruit more neutrophils and other inflammatory cells. Infiltration of T cells is also part of the granulomas. The benefit of anti-T cell therapies demonstrates the involvement of this cell in AAV. The Th1 and Th17 phenotypes are involved in the acute phase. An increase in C5a and, therefore, a participation of the alternative complement pathway has been reported ^[55].

7.3. IgA Nephropathy

IgA nephropathy (IgAN) is the main cause of renal failure due to glomerulonephritis in the world ^[56]. Components of innate immunity are also involved in this nephropathy. The deposition of IgA aggregates or IgA immune complexes and subsequent activation of T cells causing inflammation is considered the main cause of the disease. The IgA subclass deposited in the glomerulus is the IgA1, which plays the central role in the pathophysiology of the disease. Mesangial cell proliferation is the typical histological finding of IgAN. Mesangial cells undergo proliferation under the action of IL-1, among other cytokines ^[57]. The contribution of cytokines involved in the inflammasome cascade suggests a role for this inflammatory component in IgAN. The alternative complement pathway and lectin pathways are also involved in the development of the disease since C3, C4, C4d, properdin, C5b-C9 and mannose binding lectin are usually detected in renal biopsy ^[58].

7.4. Anti-Glomerular Basement Membrane Glomerulonephritis

Anti-glomerular basement membrane (anti-GBM) is an infrequent autoimmune disease that affects the small vessels of the kidneys and lungs. Patients develop antibodies against the non-collagenous domain of the α3 chain of type IV collagen present in the basal membrane of those organs ^[59]. Although the humoral immunity plays a central role, the participation of cellular immunity has also been reported. Thus, the IgG1 and IgG3 subclasses have been clearly related to the severity of the disease. The deposition of antibodies in kidney vessels can origin inflammation by activating complement and the Fc receptor. On the other hand, the increase in CD4+ T cells has been correlated with the severity of the disease. Peripheral CD4+ progress in the presence of α3 (IV) NC1. In addition, in animal models, CD4+ has been shown to be a trigger for the development of anti-GBM antibodies ^[60].