Journal
FEBS JOURNAL
Volume 286, Issue 3, Pages 507-522Publisher
WILEY
DOI: 10.1111/febs.14738
Keywords
cell death; DAMP; IL-33; MLKL; necroptosis
Categories
Funding
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Israel Science Foundation (ISF) [1416/15, 818/18]
- Alpha-1 Foundation
- United States - Israel Binational Science Foundation (BSF) [2017176]
- NIH [5RO1HL124209]
- American Asthma Foundation
- BSF [2017176]
- Naomi Foundation through the Tel Aviv University GRTF Program
Ask authors/readers for more resources
Interleukin-33 (IL-33) is a pro-inflammatory cytokine that plays a significant role in inflammatory diseases by activating immune cells to induce type 2 immune responses upon its release. Although IL-33 is known to be released during tissue damage, its exact release mechanism is not yet fully understood. Previously, we have shown that cleaved IL-33 can be detected in the plasma and epithelium of Ripk1(-/-) neonates, which succumb to systemic inflammation driven by spontaneous receptor-interacting protein kinase-3 (RIPK3)-dependent necroptotic cell death, shortly after birth. Thus, we hypothesized that necroptosis, a RIPK3/mixed lineage kinase-like protein (MLKL)-dependent, caspase-independent cell death pathway controls IL-33 release. Here, we show that necroptosis directly induces the release of nuclear IL-33 in its full-length form. Unlike the necroptosis executioner protein, MLKL, which was released in its active phosphorylated form in extracellular vesicles, IL-33 was released directly into the supernatant. Importantly, full-length IL-33 released in response to necroptosis was found to be bioactive, as it was able to activate basophils and eosinophils. Finally, the human and murine necroptosis inhibitor, GW806742X, blocked necroptosis and IL-33 release in vitro and reduced eosinophilia in Aspergillus fumigatus extract-induced asthma in vivo, an allergic inflammation model that is highly dependent on IL-33. Collectively, these data establish for the first time, necroptosis as a direct mechanism for IL-33 release, a finding that may have major implications in type 2 immune responses.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available