SHARPIN restrains IL-33 release by stromal cells to control ILC2 inflammation.

Authors

Peng Zeng, Xin Mao, Wen Zhang, Jia Li, Zhiqing Wang, Chao Zhang, Qian Li, Yun-Cai Liu

Published in

Science advances. Volume 12. Issue 35. Pages eaea2388. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

Loss of SHARPIN, a component of the linear ubiquitin chain assembly complex (LUBAC), causes systemic inflammation including the accumulation of eosinophils across multiple tissues in mice. However, the mechanisms by which SHARPIN regulates type 2 inflammation remain unclear. Here, we found that SHARPIN deficiency resulted in increased numbers of type 2 innate lymphoid cells (ILC2s) in the lung and other tissues via a cell-extrinsic mechanism. SHARPIN loss enhanced interleukin-33 (IL-33) production by lung stromal cells in vivo and in vitro, thereby promoting ILC2 proliferation. Mechanistically, SHARPIN directly bound IL-33 through its Pleckstrin homology-linker region and restrained IL-33 release independently of its ubiquitination. Combined deficiency of SHARPIN and IL-33 completely reversed ILC2 increase and lung inflammation, but not stromal cell death. Our study reveals a non-canonical, ubiquitin-independent function of SHARPIN as a gatekeeper of IL-33-driven type 2 inflammation.

PMID:
42664346
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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