E-Poster with pre-recorded video presentation Lorne Infection and Immunity 2021

IL-37 employs multiple strategies to suppress inflammasome-mediated IL-1β bioactivity and inflammation (#264)

Ina Rudloff 1 2 , Holly K Ung 1 2 , Jennifer K Dowling 3 , Ashley Mansell 4 5 , D'Andrea Laura 6 , Andrew M Ellisdon 6 , James C Whisstock 6 7 , Philip J Berger 1 2 , Claudia A Nold-Petry 1 2 , Marcel F Nold 1 2 8
  1. Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Paediatrics, Monash University, Melbourne, VIC, Australia
  3. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
  4. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  5. Department of Molecular and Translational Sciences, Monash University, Melbourne, VIC, Australia
  6. Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  7. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia
  8. Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia

Background: The interleukin (IL)-1 family member IL-37 is one of the rare anti-inflammatory cytokines, its broad and powerful inflammation-inhibiting properties are well described. However, the mechanisms of action of IL-37 are poorly defined and especially its effects on the inflammasome, a multi-protein complex required for the maturation of the pro-inflammatory IL-1β and IL-18, are not well understood.

Methods: To study how IL-37 affects the expression and inflammasome-dependent maturation of IL‑1β and IL-18, we performed gene expression analyses as well as inflammasome activation assays (ASC oligomerization/speck assays, caspase-1 assays) in bone marrow-derived macrophages (BMDM) of IL-37-transgenic and wild-type mice. Moreover, we investigated the effects of IL-37 on pyroptosis, an inflammatory form of cell death, by gene expression analyses and lactate dehydrogenase release assays in activated BMDM. Employing an endotoxemia model, we also investigated the role of IL-37 in vivo.

Results: IL-37 inhibited IL-1β production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect LPS-induced mRNA expression of Il18 or inflammasome components, IL‑37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, IL‑37 suppressed nigericin- and silica-induced ASC oligomerization/speck formation (a step required for inflammasome activity) and subsequent caspase-1 activation. IL-37 also inhibited pyroptosis (50% reduction); and in mice subjected to endotoxemia, IL-37 reduced the abundance of plasma IL-1β (78% reduction compared to wild-type animals) and IL‑18 (61% reduction).

Conclusion: Our study adds to the portfolio of anti-inflammatory pathways employed by IL-37. We demonstrate that IL-37 uses multiple strategies to suppress the bioactivity of inflammasomes and consequently of IL-1β and IL-18. Moreover, we identify IL-37 as an inhibitor of inflammation-amplifying pyroptosis. Importantly, our results highlight IL-37 as a potential tool for treating inflammasome-driven, hyper-inflammatory diseases.