Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses
Ana Maria Bulau,Marcel F. Nold,Suzhao Li,Claudia A. Nold-Petry,Michaela Fink,Ashley Mansell,Tobias Schwerd,Jaewoo Hong,Anna Rubartelli,Charles A. Dinarello,Charles A. Dinarello,Philip Bufler +11 more
TLDR
It is shown that caspase-1 processing is required for maturation of the intracellular IL-37 precursor for its translocation to the nucleus, and that neutralizing antibodies reverse the suppression of LPS-induced IL-6 inIL-37 transgenic mice, supporting a role for extracellular signaling by IL- 37.Abstract:
IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37–mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrow-derived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck-like protein containing a carboxyl-terminal caspase recruitment domain- and NLRP3-deficient cells does not reduce levels of IL-6 and IL-1β upon LPS stimulation. IL-37–expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL-37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37–neutralizing antibodies before LPS challenge. In IL-37–expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual-function cytokine with intra- and extracellular properties for suppressing innate inflammation.read more
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IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
Claudia A. Nold-Petry,Camden Lo,Ina Rudloff,Kirstin Elgass,Suzhao Li,Michael P. Gantier,Amelie S. Lotz-Havla,Søren W. Gersting,Steven X. Cho,Jason C. Lao,Andrew M. Ellisdon,Björn Rotter,Tania Azam,Niamh E. Mangan,Fernando J. Rossello,James C. Whisstock,Philip Bufler,Cecilia Garlanda,Alberto Mantovani,Charles A. Dinarello,Marcel F. Nold +20 more
TL;DR: Nold et al. as mentioned in this paper identified the receptor for IL-37 and clarified the molecular nature of the anti-inflammatory pathway induced by this cytokine, which is a member of the IL-1 family.
Journal Article
IL-37 requires the receptors IL-18Ra and IL-1R8 (SIGIRR) to carry out its multi-faceted anti-inflammatory program on innate signal transduction
C. Nold,C. Lo,I Rudloff,K. Elgass,Suzhao Li,Michael P. Gantier,A. Lotz-Hayla,S. Gersting,S. Cho,J. Lao,A. Ellisdon,B. Rotter,T. Azam,Niamh E. Mangan,F. Rosello,J. Whisstock,Philip Bufler,Cecilia Garlanda,Alberto Mantovani,Charles A. Dinarello,Marcel F. Nold +20 more
TL;DR: Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases.
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