The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (49), p.e2302903120-e2302903120
• Main Authors: Kumagai, Jin, Kiuchi, Masahiro, Kokubo, Kota, Yagyu, Hiroyuki, Nemoto, Masahiro, Tsuji, Kaori, Nagahata, Ken, Sasaki, Atsushi, Hishiya, Takahisa, Onoue, Miki, Shinmi, Rie, Sonobe, Yuri, Iinuma, Tomohisa, Yonekura, Syuji, Shinga, Jun, Hanazawa, Toyoyuki, Koseki, Haruhiko, Nakayama, Toshinori, Yokote, Koutaro, Hirahara, Kiyoshi
• Format: Article
• Language: English
• Subjects: Allergic diseases; Animals; Biological Sciences; CD4 antigen; Cell Differentiation; Clonal deletion; Differentiation (biology); Endopeptidases; Granzyme B; Granzymes - genetics; Granzymes - metabolism; Helper cells; Humans; Hypersensitivity; Inflammation; Inflammation - metabolism; Interleukin 5; Interleukin-5 - metabolism; Kinases; Leukocytes (eosinophilic); Lymphocytes; Lymphocytes T; MAP kinase; Mice; Pathophysiology; Phosphorylation; Polyps; Protease; Proteinase-activated receptor 1; Respiratory tract diseases; Rhinosinusitis; Serine proteinase; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Th2 Cells; Therapeutic targets; Ubiquitin-Specific Peptidase 7 - metabolism; Ubiquitin-specific proteinase
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2302903120

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 or 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.