Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8

Abstract

Similar to IL-1α and IL-33, IL-1 family member IL-37b translocates to the nucleus and is associated with suppression of innate and adaptive immunity. Here we demonstrate an extracellular function of the IL-37 precursor and a processed form. Recombinant IL-37 precursor reduced LPS-induced IL-6 by 50% (P < 0.001) in highly inflammatory human blood-derived M1 differentiated macrophages derived from selective subjects but not M2 macrophages. In contrast, a neutralizing monoclonal anti-IL-37 increased LPS-induced IL-6, TNFα and IL-1β (P < 0.01). The suppression by IL-37 was consistently observed at low picomolar but not nanomolar concentrations. Whereas LPS induced a 12-fold increase in TNFα mRNA, IL-37 pretreatment decreased the expression to only 3-fold over background (P < 0.01). Mechanistically, LPS-induced p38 and pERK were reduced by IL-37. Recombinant IL-37 bound to the immobilized ligand binding α-chain of the IL-18 receptor as well as to the decoy receptor IL-1R8. In M1 macrophages, LPS increased the surface expression of IL-1R8. Compared with human blood monocytes, resting M1 cells express more surface IL-1R8 as well as total IL-1R8; there was a 16-fold increase in IL-1R8 mRNA levels when pretreated with IL-37. IL-37 reduced LPS-induced TNFα and IL-6 by 50-55% in mouse bone marrow-derived dendritic cells, but not in dendritic cells derived from IL-1R8-deficient mice. In mice subjected to systemic LPSinduced inflammation, pretreatment with IL-37 reduced circulating and organ cytokine levels. Thus, in addition to a nuclear function, IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties., previously known as IL-1 family member 7, broadly reduces innate inflammation as well as acquired immune responses (1). In human peripheral blood mononuclear cells (PBMCs), a knockdown of endogenous IL-37 results in increased production of LPS-as well as IL-1β-induced cytokines (2). Mice transgenic for full-length human IL-37 (IL-37tg) are protected against LPS-induced systemic inflammation (2), chemical colitis (3), metabolic syndrome (4), and acute myocardial infarction (5). IL-37tg mice also have suppressed immune responses following challenge by specific antigen (6). We believe that full-length IL-37 expressed in the transgenic mice is processed extracellularly.In mouse macrophages stably transfected with human IL-37, ∼20% of IL-37 translocates to the nucleus (7), which is associated with decreased cytokine production (2, 7). However, in the presence of a caspase-1 inhibitor, there is no translocation to the nucleus and no reduction in LPS-induced cytokines (7). Mutation of aspartic acid at the caspase-1 cleavage position 20 to alanine also results in failure to translocate to the nucleus and loss of the suppression of cytokine production (8). Thus, as with IL-1α and IL-33, IL-37 is the third member of the IL-1 family that translocates to the nucleus and affects cellular responses. Nevertheless, it remains unclear whether the reduction in cytokin...

IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17–Triggering Cytokine Production and Limiting Th17 Cell Proliferation

“…Notably, the importance of IL-37 in modulating the inflammatory response is also supported by recent data showing that decreased IL-37 expression in patients with Behçet's disease triggers the Th17-inflammation response (29). Although the molecular mechanism of IL-37 in autoimmune disease remains unknown, recent studies showed that IL-37 acts as an extracellular cytokine by binding IL-18R and IL-1R8 for its anti-inflammatory properties (30). In addition, IL-37 fails to inhibit IL-17-triggering cytokine (IL-1b and IL-6) production and the MAPK signaling pathway in DCs from IL-1R8-deficient mice (30).…”

“…Although the molecular mechanism of IL-37 in autoimmune disease remains unknown, recent studies showed that IL-37 acts as an extracellular cytokine by binding IL-18R and IL-1R8 for its anti-inflammatory properties (30). In addition, IL-37 fails to inhibit IL-17-triggering cytokine (IL-1b and IL-6) production and the MAPK signaling pathway in DCs from IL-1R8-deficient mice (30). A recent study showed that IL-17 expression was dramatically enhanced in IL-1R8-deficient mice (31).…”

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

“…Thus, SIGIRR has long been considered as an orphan receptor with unknown ligand molecules. Recently, human SIGIRR was found to act as a coreceptor with IL-18Ra for the recognition of IL-37, uncovering the existence of a previously unknown mechanism underlying the SIGIRR-mediated inflammatory regulation (3,53). Although well identified in mammals and predicted to be conserved from chicken to humans on the basis of sequence and expression patterns (54), the occurrence and existence of the SIGIRR homolog in lower vertebrates, including teleost fish, are poorly understood.…”

Protective effect of the polarity of macrophages regulated by IL-37 on atherosclerosis

“…Current studies have demonstrated that such functions of IL-37 are mainly related to its inhibition of the release of inflammatory cytokines, including IL-1β, IL-18, and TNF-α (Li et al, 2015;Nold-Petry et al, 2015). For example, IL-37 can potentiate the inhibitory function of IL-18BP on IL-18 via specific binding (Bufler et al, 2004).…”