Interleukin 37 limits monosodium urate crystal-induced innate immune responses in human and murine models of gout

Abstract

BackgroundInterleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models.MethodsWe investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model. After inhibition of Mer receptor tyrosine kinase (Mertk), levels of IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL-2) were detected by ELISA and expression of mammalian homologs of the drosophila Mad gene 3 (Smad), suppressor of cytokine signaling 3 (SOCS3), NACHT-LRR-PYD-containing protein 3 (NLRP3), and IL-8R of THP-1 were assessed by qPCR and western blot to explore the molecular mechanisms.ResultsOur studies strongly indicated that rhIL-37 played a potent immunosuppressive role in the pathogenesis of experimental gout models both in vitro and in vivo, by downregulating proinflammatory cytokines and chemokines, markedly reducing neutrophil and monocyte recruitment, and mitigating pathological joint inflammation. In our studies, rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to block inflammation, including inhibition of NLRP3 and activation of SOCS3. Mertk signaling participated in rhIL-37 inhibitory pathways in gout models. By inhibition of Mertk, the anti-inflammatory effect of rhIL-37 was partly abrogated, and IL-1R8, Smad3 and S​OCS3 expression were suppressed, whereas NLRP3 expression was reactivated.ConclusionsOur studies reveal that IL-37 limits runaway inflammation initiated by MSU crystal-induced immune responses, partly in a Mertk-dependent fashion. Thus, rhIL-37 has both preventive and therapeutic effects in gouty arthritis.

Parsing the IL-37-Mediated Suppression of Inflammasome Function

“…It is tempting to speculate that patients suffering from severe IL-1β-and inflammasome-driven inflammatory diseases would benefit from the development of anti-inflammatory therapies employing IL-37. In fact, IL-37 has been shown to ameliorate inflammation in experimental gout [64] and to be protective against obesity-induced inflammation and insulin resistance that can lead to type II diabetes [35].…”

Estradiol inhibits NLRP3 inflammasome in fibroblast‐like synoviocytes activated by lipopolysaccharide and adenosine triphosphate

“…Many regulation factors of NLRP3 inflammasomes are being studied, such as A20 negatively regulated NLRP3, clematichinenoside AR‐inhibited succinate accumulation affected by tumor growth factor‐β1, including estrogen, which was related with the development of knee OA. The regulation of estrogen on NLRP3 inflammasome had been studied in several diseases, whereas the underlying mechanism was undefined.…”

What makes gouty inflammation so variable?

“…IL-37, a member of the IL-1 family, is an anti-inflammatory cytokine differentially regulated during the course of tissue inflammatory reactions, largely through expression by epithelial cells and mononuclear leukocytes [ 55 , 56 ]. IL-37 suppresses multiple innate inflammatory responses in vitro and in vivo, acting partially via inhibition of the NLRP3 inflammasome and activation of suppressor of cytokine signaling 3 [ 55 ]. IL-37 actions are mediated partly by the phosphatidylserine receptor Mer receptor tyrosine kinase signaling, and enhanced expression of IL-1R8 [ 55 ].…”

“…IL-37 suppresses multiple innate inflammatory responses in vitro and in vivo, acting partially via inhibition of the NLRP3 inflammasome and activation of suppressor of cytokine signaling 3 [ 55 ]. IL-37 actions are mediated partly by the phosphatidylserine receptor Mer receptor tyrosine kinase signaling, and enhanced expression of IL-1R8 [ 55 ]. Exogenous human IL-37 markedly suppresses experimental urate crystal-induced inflammation in mice [ 55 ].…”

“…IL-37 actions are mediated partly by the phosphatidylserine receptor Mer receptor tyrosine kinase signaling, and enhanced expression of IL-1R8 [ 55 ]. Exogenous human IL-37 markedly suppresses experimental urate crystal-induced inflammation in mice [ 55 ]. In a recent study of PBMCs from subjects with acute gout, non-acute gout, non-acute gouty arthritis, and healthy controls, IL-37 was reported as significantly greater in the non-acute gouty arthritis patients compared to acute gout and healthy controls [ 56 ], which is in contrast to increases in IL-1β, IL-6, and TNFα in the acute gout group.…”