title: Interleukin 37 limits monosodium urate crystal-induced innate immune responses in human and murine models of gout.
abstract: Interleukin (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.
  
  
  
  We 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.
  
  
  
  Our 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.
  
  
  
  Our 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.
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Pathology, North Huashan Hospital, Fudan University, 108# Luqiang Road, Baoshan District, Shanghai, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Xuan
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Minrui
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China. drzhangjiong@sina.com.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China. drzhangjiong@sina.com.
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, Huashan Hospital, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China. hjzou@fudan.edu.cn.|Institute of Rheumatology, Immunology and Allergy, Fudan University, 12# Wulumuqi Road, Jingan District, Shanghai, China. hjzou@fudan.edu.cn.
authors.forename: Hejian
authors.initials: H
authors.lastname: Zou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006073:Gout / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000276:immunology; D014527:Uric Acid / Q000276:immunology*
chemical_list: C508587:IL37 protein, human; D007375:Interleukin-1; D011994:Recombinant Proteins; D014527:Uric Acid
keywords: Gout; IL-1R8; IL-37; MSU; Mertk; NLRP3; Smad3; S​OCS3