Journal
CELL DEATH & DISEASE
Volume 12, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-020-03332-w
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Funding
- National Research Foundation of Korea (NRF) [2020R1A5A2019210, 2020R1A2B5B02001686]
- Korean government (MSIT)
- National Research Foundation of Korea [2020R1A5A2019210] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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AIM plays a crucial role in inhibiting inflammasome-mediated caspase-1 activation and IL-1 beta and IL-18 production. IL-10 induces AIM expression by regulating STAT3 activity, leading to anti-inflammatory effects.
Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1 beta production and caspase-1 activation by IL-10 was reversed in BMDM from AIM(-/-) mice. Treatment of BMDM from both wild type (WT) and IL-10(-/-) mice with recombinant AIM showed the inhibitory effects on IL-1 beta and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1 beta and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM(-/-) mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1 beta and IL-18 production.
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