1. The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.
- Author
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Kumagai J, Kiuchi M, Kokubo K, Yagyu H, Nemoto M, Tsuji K, Nagahata K, Sasaki A, Hishiya T, Onoue M, Shinmi R, Sonobe Y, Iinuma T, Yonekura S, Shinga J, Hanazawa T, Koseki H, Nakayama T, Yokote K, and Hirahara K
- Subjects
- Humans, Animals, Mice, Granzymes genetics, Granzymes metabolism, Interleukin-5 metabolism, Ubiquitin-Specific Peptidase 7 metabolism, Inflammation metabolism, Cell Differentiation, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Th2 Cells, Hypersensitivity
- Abstract
Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4
+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2023
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