Higher susceptibility of males to bleomycin-induced pulmonary inflammation is associated with sex-specific transcriptomic differences in myeloid cells.
Higher susceptibility of males to bleomycin-induced pulmonary inflammation is associated with sex-specific transcriptomic differences in myeloid cells.
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雄性对博来霉素诱导的肺部炎症的敏感性更高，与髓样细胞中性别特异性的转录组差异有关。
DOI：
10.1016/j.taap.2022.116228
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发表时间：
2022-11-01
影响因子：
3.8
通讯作者：
Saini Y
中科院分区：
文献类型：
--
作者：
Lamichhane R;Patial S;Saini Y
特发性肺纤维化是一种可能有遗传和环境原因的疾病，在人类男性中相对更常见，预后较差。然而，这些与性别相关的纤维化严重程度差异的潜在机制仍不清楚。在这里，我们测试了一种假设，即髓系细胞的转录调控谱决定了雄性小鼠对博莱霉素(BLM)诱导的肺纤维化的更高易感性。成年小鼠口咽内注射生理盐水或博莱霉素。评估肺损伤、炎症和纤维化结果，并对空隙髓系细胞进行RNA测序。与雌性小鼠相比，雄性小鼠肺损伤、炎症、促炎细胞因子(IL-6、IL-1β、IL-7和IP-10)和纤维化程度明显增加。有趣的是，在生理盐水对照组中，一些促炎基因和细胞外基质相关基因在男性髓系细胞中比女性髓系细胞显著上调。类似地，与女性髓系细胞相比，BLM攻击导致男性的促炎和促纤维化的转录改变更大。另一方面，与各自的生理盐水对照组相比，抗炎和调节细胞因子IL10和IFNG分别在BLM攻击的女性髓系细胞中上调，而在男性髓系细胞中没有上调。进一步的跨性别骨髓移植实验显示，雄性造血祖细胞(HPC)增加了雌性小鼠的粒细胞浸润，而雌性HPC则减少了雄性小鼠的粒细胞渗透。这些发现表明，雄性和雌性肺髓系细胞之间存在固有的转录差异，雄性髓系细胞的促炎性质足以增加雌性小鼠对博莱曼诱导的炎症的易感性。
Idiopathic pulmonary fibrosis, a condition with likely genetic and environmental etiology, is relatively more prevalent with poor prognosis in human males. However, the underlying mechanisms for these gender-associated differences in the severity of fibrosis remain unknown. Here, we tested the hypothesis that the transcriptomic repertoire of myeloid cells determines the higher susceptibility of male mice to bleomycin (BLM)-induced lung fibrosis. Adult mice were oropharyngeally challenged with saline or BLM. Lung injury, inflammation, and fibrosis outcomes were assessed, and airspace myeloid-cells were subjected to RNA-sequencing. As compared with the female mice, the male mice manifested significantly increased lung injury, inflammation, proinflammatory cytokines (IL-6, IL-1β, IL-7, and IP-10), and fibrosis in response to BLM challenge. Interestingly, several pro-inflammatory and extracellular matrix-associated genes were significantly up-regulated in male myeloid-cells compared to female myeloid-cells in the saline-control group. Similarly, BLM challenge resulted in greater pro-inflammatory and pro-fibrotic transcriptomic changes in male compared to female myeloid cells. On the other hand, anti-inflammatory and regulatory cytokine, Il10 and Ifng respectively, were uniquely upregulated in BLM-challenged female but not in male myeloid cells when compared to their respective saline-control groups. Further, cross-sex bone marrow transplantation experiments revealed that male hematopoietic progenitor cells (HPCs) increased the granulocytic infiltration in female mice while female HPCs decreased the granulocytic infiltration in male mice post-BLM challenge. These findings suggest that there are inherent transcriptomic differences between the male and female lung myeloid cells and that the pro-inflammatory nature of male myeloid cells is sufficient to increase the susceptibility of female mice to BLM-induced inflammation.
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DOI：
10.1084/jem.20162152
发表时间：
2017-08-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Misharin AV;Morales-Nebreda L;Reyfman PA;Cuda CM;Walter JM;McQuattie-Pimentel AC;Chen CI;Anekalla KR;Joshi N;Williams KJN;Abdala-Valencia H;Yacoub TJ;Chi M;Chiu S;Gonzalez-Gonzalez FJ;Gates K;Lam AP;Nicholson TT;Homan PJ;Soberanes S;Dominguez S;Morgan VK;Saber R;Shaffer A;Hinchcliff M;Marshall SA;Bharat A;Berdnikovs S;Bhorade SM;Bartom ET;Morimoto RI;Balch WE;Sznajder JI;Chandel NS;Mutlu GM;Jain M;Gottardi CJ;Singer BD;Ridge KM;Bagheri N;Shilatifard A;Budinger GRS;Perlman H
通讯作者：
Perlman H
影响因子：
8.6
作者：
Pechkovsky, Dmitri V.;Prasse, Antje;Zissel, Gernot
通讯作者：
Zissel, Gernot
DOI：
10.1089/jamp.2011.0919
发表时间：
2012-04-01
影响因子：
3.4
作者：
Diaz, Keith T.;Skaria, Shibu;Condos, Rany
通讯作者：
Condos, Rany
影响因子：
3.9
作者：
Desai O;Winkler J;Minasyan M;Herzog EL
通讯作者：
Herzog EL
影响因子：
4.6
作者：
Caminati, Antonella;Madotto, Fabiana;Harari, Sergio
通讯作者：
Harari, Sergio