A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit

被引：13

作者：

Benamar, Mehdi ^{[1
,2
]}

Harb, Hani ^{[1
,2
,3
]}

Chen, Qian ^{[1
,2
]}

Wang, Muyun ^{[1
,2
]}

Chan, Tsz Man Fion ^{[1
,2
]}

Fong, Jason ^{[1
,2
]}

Phipatanakul, Wanda ^{[1
,2
]}

Cunningham, Amparito ^{[1
,2
]}

Ertem, Deniz ^{[1
,2
]}

Petty, Carter R. ^{[4
]}

Mousavi, Amirhosein J. ^{[5
]}

Sioutas, Constantinos ^{[5
]}

Crestani, Elena ^{[1
,2
]}

Chatila, Talal A. ^{[1
,2
]}

机构：

[1] Boston Childrens Hosp, Div Immunol, Boston, MA USA

[2] Harvard Med Sch, Dept Pediat, Boston, MA USA

[3] Tech Univ Dresden, Inst Med Microbiol & Virol, Dresden, Germany

[4] Boston Childrens Hosp, Inst Ctr Clin & Translat Res, Boston, MA USA

[5] Univ Southern Calif, Dept Civil & Environm Engn, Los Angeles, CA USA

来源：

ALLERGY | 2022年 / 77卷 / 11期

基金：

美国国家卫生研究院;

关键词：

asthma; GRB2; interleukin; 4; receptor; Notch4; regulatory T cells; INNER-CITY ASTHMA; AIRWAY INFLAMMATION; IL4R VARIANT; GALA II; RISK; SUSCEPTIBILITY; ASSOCIATION; ENVIRONMENT; POLLUTION; CHILDREN;

D O I：

10.1111/all.15444

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4R alpha R576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T-reg) cells in an IL-6-dependent manner. Objective We examined the interaction between IL-4R alpha R576 and Notch4 in promoting asthmatic inflammation. Methods Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on T-reg cells as a function of IL4R(R576) allele. The capacity of IL-4R alpha R576 to upregulate Notch4 expression on T-reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. Results Asthmatics carrying the IL4R(R576) allele had increased Notch4 expression on their circulating T-reg cells as a function of disease severity and serum IL-6. Mice harboring the Il4ra(R576) allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon T-reg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4R alpha R576 upregulated the expression in lung T-reg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. Conclusion These results identify an IL-4R alpha R576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung T-reg cell function.

引用

页码：3377 / 3387

页数：11