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

被引：9

作者：

Kumagai, Jin ^{[1
,2
]}

Kiuchi, Masahiro ^{[1
]}

Kokubo, Kota ^{[1
]}

Yagyu, Hiroyuki ^{[1
]}

Nemoto, Masahiro ^{[1
]}

Tsuji, Kaori ^{[1
]}

Nagahata, Ken ^{[1
,3
]}

Sasaki, Atsushi ^{[1
]}

Hishiya, Takahisa ^{[1
]}

Onoue, Miki ^{[1
]}

Shinmi, Rie ^{[1
]}

Sonobe, Yuri ^{[1
]}

Iinuma, Tomohisa ^{[4
]}

Yonekura, Syuji ^{[4
]}

Shinga, Jun ^{[5
]}

Hanazawa, Toyoyuki ^{[4
]}

Koseki, Haruhiko ^{[6
]}

Nakayama, Toshinori ^{[1
]}

Yokote, Koutaro ^{[2
]}

Hirahara, Kiyoshi ^{[1
,7
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba 2608670, Japan

[2] Chiba Univ, Grad Sch Med, Dept Endocrinol Hematol & Gerontol, Chiba 2608670, Japan

[3] Sapporo Med Univ, Dept Rheumatol, Sapporo 0608556, Japan

[4] Chiba Univ, Grad Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Chiba 2608670, Japan

[5] RIKEN, Ctr Integrat Med Sci, Lab Immunotherapy, Yokohama, Kanagawa 2300045, Japan

[6] Chiba Univ, Grad Sch Med, Dept Cellular & Mol Med, Chiba 2608670, Japan

[7] Chiba Univ, Synergy Inst Futurist Mucosal Vaccine Res & Dev, Chiba 2608670, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 49期

关键词：

pathogenic Th2; ubiquitin specific protease 7 (USP7); granzyme; signal transducers and activators of transcription (STAT)3; asthma; intractable allergic disease; TRANSCRIPTION; GRANZYMES; HAUSP; INHIBITION; EXPRESSION; APOPTOSIS; FATE; IL-4; P53;

D O I：

10.1073/pnas.2302903120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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