Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Beh?et's uveitis

作者全名：Wang, Qingfeng; Ma, Junfeng; Gong, Yuxing; Zhu, Lifu; Tang, Huanyu; Ye, Xingsheng; Su, Guannan; Huang, Fanfan; Tan, Shiyao; Zuo, Xianbo; Gao, Yuan; Yang, Peizeng

作者地址：[Wang, Qingfeng; Ma, Junfeng; Ye, Xingsheng; Su, Guannan; Huang, Fanfan; Tan, Shiyao; Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [Ma, Junfeng; Zhu, Lifu; Tang, Huanyu; Gao, Yuan] Third Mil Med Univ, Southwest Eye Hosp, Southwest Hosp, Chongqing, Peoples R China; [Ma, Junfeng; Zhu, Lifu; Tang, Huanyu; Gao, Yuan] Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing, Peoples R China; [Gong, Yuxing; Gao, Yuan] Shanxi Med Univ, Translat Med Res Ctr, Taiyuan, Shanxi, Peoples R China; [Zuo, Xianbo] China Japan Friendship Hosp, Beijing, Peoples R China; [Zuo, Xianbo] Anhui Med Univ, Hosp 1, Anhui, Peoples R China

通信作者：Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China.; Gao, Y (通讯作者)，Third Mil Med Univ, Southwest Eye Hosp, Southwest Hosp, Chongqing, Peoples R China.; Gao, Y (通讯作者)，Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing, Peoples R China.; Gao, Y (通讯作者)，Shanxi Med Univ, Translat Med Res Ctr, Taiyuan, Shanxi, Peoples R China.

来源：CELL DISCOVERY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001221462100001

JCR分区：Q1

影响因子：13

年份：2024

卷号：10

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要：Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-alpha responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Beh & ccedil;et's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.

基金机构：National Natural Science Foundation of China (National Science Foundation of China) [82230032, 81930023]; National Natural Science Foundation Key Program [2019YFA0111200, 2020YFA0113500]; National Key R&D Program of China [81970774, 81600709, 82101106]; National Natural Science Foundation of China [CSTC2021jscx-gksb-N0010]; Key Project of Chongqing Science and Technology Bureau [cstc2016jcyjA0598, cstc2017jcyjBX0058]; Natural Science Foundation of Chongqing City; Chongqing Outstanding Scientists Project 2019 [202103021221008]; Fundamental Research Program of Shanxi Province [202204051001023]; Shanxi Province Science and Technology Innovation Team Project

基金资助正文：We thank Deepak A. Lamba for his excellent discussion and comments. We thank Jinyu Cai and Qingyan Jiang for assistance in collecting the metadata of participations. We thank Qiang Tan and Qinfeng Ma (Knorigene Technologies company) for assistance in processing scRNA-seq raw data as we required. We thank Qingfeng Cao, Changwei Huang, Yujie Lai, Chunjiang Zhou and Yao Wang for assistance in collecting samples. This research was supported by grants from the National Natural Science Foundation Key Program (82230032 and 81930023 to P.Y.), the National Key R&D Program of China (2019YFA0111200 and 2020YFA0113500 to Y.G.), the National Natural Science Foundation of China (81970774 and 81600709 to Y.G., and 82101106 to Q.W.), the Key Project of Chongqing Science and Technology Bureau (CSTC2021jscx-gksb-N0010 to P.Y.), the Natural Science Foundation of Chongqing City (cstc2016jcyjA0598 and cstc2017jcyjBX0058 to Y.G.), Chongqing Outstanding Scientists Project 2019 to P.Y., Chongqing Chief Medical Scientist Project 2018 to P.Y., the Fundamental Research Program of Shanxi Province (202103021221008 to Y.G.), and Shanxi Province Science and Technology Innovation Team Project (202204051001023 to Y.G.).