SIGIRR: single immunoglobulin IL-1R-related molecule; TIR: toll-IL1R; IL1RAPL1 and IL1RAPL2: IL-1 receptor accessory protein like 1 and 2; TIGIRR 1 and 2: three immunoglobulin domain-containing IL-1 receptor-related 1 and 2. To produce their pro-inflammatory functions, IL-1 cytokines form complexes with their respective receptor and a co-receptor (Figure 1). All of them except IL-1Ra are synthesized as precursors and require N-terminal processing in order to acquire their full function ^[3][4][3,4]. They can be activated both extracellularly by proteolytic cleavage and intracellularly via inflammasome-mediated cleavage [5]. Binding of cleaved IL-1α/β to the extracellular domain of IL-1R1 leads to recruitment of IL-1RAcP, resulting in the initiation of a signaling cascade with the recruitment of the myeloid differentiation primary response 88 (MyD88) accessory protein and Interleukin 1 receptor-associated kinases (IRAKs). This in turn results in activation of the nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs), ultimately resulting in pro-inflammatory gene expression [6]. Furthermore, IL-1 signaling also induces activation of defense mechanisms (antigen recognition, phagocytosis, degranulation, and nitric oxide production) and activates lymphocyte functions implicated in adaptive immunity, thus acting as a link between innate and adaptive immune responses [7]. The other IL-1 family cytokines IL-33, IL-18, and IL-36α/β/γ form similar ternary complexes with their respective receptors and co-receptors and also act through Myd88 to induce pro-inflammatory gene expression. Regulatory mechanisms are necessary to maintain homeostasis; they include decoy receptors, receptor antagonists, and anti-inflammatory cytokines (Figure 1). IL-1R2 is a cytoplasmic soluble receptor without a functional TIR domain that binds to IL-1α/β precursors, preventing their processing and secretion. Under proinflammatory conditions, IL-1R2 is cleaved by an inflammasome-dependent mechanism ^[8][9][8,9]. Likewise, the soluble ST2 receptor (sST2) and the soluble protein IL-18 binding protein (IL-18BP) bind to IL-33 and IL-18, respectively, neutralizing their activities ^[10][11][10,11]. Furthermore, receptor antagonists IL-1Ra, IL-36Ra, and IL-38 compete with IL-1α/β and IL-36α/β/γ [4]. Lastly, IL-37 binding to IL-18Rα leads to recruitment of the IL-1R8 co-receptor (also called single immunoglobulin IL-1R-related molecule (SIGIRR), with activation of the inhibitory STAT3 signaling pathway [12].

2.1. IL-1 Subfamily

IL-1α and IL-β are both pro-inflammatory cytokines with some distinctive characteristics. IL-1α is constitutively expressed in hematopoietic immune cells and other cell types such as intestinal epithelial cells and cutaneous keratinocytes (KCs) [13]. Although non-processed full-length IL-1α has some functional activity, cleavage by calpain and extracellular proteases such as neutrophil elastase, granzyme B, and mast cell chymase enhances its pro-inflammatory activity ^[14][15][14,15]. Its major role is played locally, since IL-1α is mostly found bound to membranes. It is also expressed intracellularly in the cytosol—acting as an alarmin upon release from necrotic cell death—and in the nucleus—activating transcription of pro-inflammatory genes or tissue homeostasis and repair genes [16]. In addition, IL-1α expression can be induced by proinflammatory stimuli, leading to IL-1R1 binding and pro-inflammatory gene expression targeting type 1 or type 17 immune responses. In turn, this produces recruitment and activation of T cells, dendritic cells (DCs), neutrophils, and monocytes/macrophages that will release further pro-inflammatory cytokines and chemokines, leading to an autoinflammatory amplification loop [17]. On the contrary, IL-1β is the primary circulating form, and its expression is inducible only in monocytes, macrophages, and DCs [17]. Full-length IL-1β precursor protein (pro-IL-1β) is stored in the cytoplasm and is cleaved by caspase-1 to its active form in response to activation of pattern recognition receptors (PPR) by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) in an inflammasome-dependent process [18]. In addition, pro-IL-1β can also be activated in the extracellular space by neutrophils and mast cells-derived proteases or by microbial proteases [19]. The antagonist IL-1Ra exerts its anti-inflammatory properties by binding to the IL-1R1 receptor and competing with IL-1α and IL-β [20].

2.2. IL-18 Subfamily

IL-18 is also a pro-inflammatory cytokine and is constitutively expressed in its inactive form in several cell types, mainly KCs, epithelial, and endothelial cells [21]. Its activation can be produced intracellularly by caspase-1-mediated cleavage or extracellularly by neutrophil or cytotoxic cell-derived proteases ^[21][22][21,22]. IL-18 pro-inflammatory activity is mainly mediated through IFNγ, but it can induce both Th1 and Th2 cellular responses [23]. In combination with IL-12 and IL-15, IL-18 stimulates Th1 cells and induces NK cell effector function and IFNγ expression ^[24][25][24,25]; in the absence of these cytokines, IL-18 induces a Th2 response with mast cell and basophil activation, ultimately ending in IL-4 and IL-13 production [26]. Moreover, when combined with IL-23, IL-18 activates Th17 cells and induces IL-17 production [27]. IL-18-BP regulates IL-18 pro-inflammatory activity by binding and sequestering the cytokine. IL-18-BP expression is induced by IFNγ, thus creating a negative feedback mechanism and decreasing inflammation [11].

2.3. IL-33 Subfamily

IL-33 is also constitutively expressed in many organs, mainly by fibroblasts, endothelial cells, and epithelial cells; its expression can also be induced in mast cells and DCs in the context of inflammation. Similar to IL-1α, IL-33 requires cleavage to increase its activity and has a dual role: intracellular gene expression regulating homeostasis and extracellular recruitment and activation of immune cells upon cell necrosis and inflammation (alarmin function) ^[28][29][28,29]. Th2 cells, mast cells, and eosinophils express the IL-33 receptor, ST2, or IL1-1RL1 [28]. IL-33 is a promoter of Th2 immunity and allergic responses, inducing production of IL-4, IL-5, and IL-13, polarization of macrophages and degranulation of mast cells, basophils, and eosinophils with cytokine and chemokine release [30]. Finally, IL-33 also acts on T-reg cells, DCs, and NK cells [31].

2.4. IL-36 Subfamily

The IL-36 subfamily is a key regulator of the innate immune system and includes three agonists with pro-inflammatory activity (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36RN or IL-36Ra and IL-38) [32]. They are normally expressed in epithelial and immune cells; after binding to receptor complex IL-36R, agonists induce activation of nuclear factor-kB (NF-kB) and mitogen-activated protein kinases, leading to T-cell proliferation, expression of pro-inflammatory cytokines, chemokines, and co-stimulatory molecules by DCs and Th1 lymphocytes, as well as autocrine KCs signaling. The resulting pro-inflammatory milieu is composed of IL-1β, IL-12, IL-23, IL-6, TNF-α, CCL1, CXCL1, CXCL2, CXCL8, and GM-CSF, among others [32]. IL-36α and IL-36γ are mainly produced by KCs but also by dermal fibroblasts, endothelial cells, macrophages, LCs, and DCs. As opposed to other IL-1 family cytokines, IL-36 cytokines are also produced as precursors but do not contain a caspase cleavage site. Following secretion, they are activated by neutrophil-derived proteases present at neutrophil extracellular traps (NETs)—such as elastase, cathepsin G, and proteinase 3—and by cathepsin S, produced by KCs and fibroblasts ^[33][34][35][33,34,35]. In addition, KCs secrete the protease inhibitors alpha-1-antitrypsin and alpha-1-antichymotrypsin (encoded by SERPINA1 and SERPINA3 genes), which inhibit processing of IL-36 cytokines by neutrophil proteases and thus regulate the inflammatory loop [36].

2.5. IL-37 and IL-38: Antagonist Cytokines

IL-37 acts as an anti-inflammatory cytokine and is constitutively expressed mainly in KCs, but can be induced in monocytes/macrophages, T cells, and B cells. It has a dual action, depending on extracellular or intracellular signaling. Extracellularly, IL-37 binds IL-18Rα and recruits IL-1R8 to form the IL-37/IL-1R8/IL-18Rα complex, restricting IL-18R-dependent inflammation and inhibiting innate immunity [12]. In the cytosol, IL-37 cleaved by caspase-1 translocates to the nucleus to bind Smad transcription factors, ultimately decreasing pro-inflammatory cytokine production. The precursor exhibits activity, but cleaved IL-37 binds more effectively to its receptor [37]. IL-38 also acts as an anti-inflammatory cytokine and is expressed in skin and various immune cells, such as B cells. It specifically binds to IL-36R and inhibits human mononuclear cells stimulated with IL-36 in vitro [38]. IL-38 expression is inhibited by IL-17, IL-22, and IL-36γ [4]. Furthermore, IL-38 is able to suppress the production of IL-17A by γδ T-cells through IL-1RAcP antagonism [39].