Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation
Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation
ABSTRACT Tissue injury leads to activation of resident stromal, parenchymal and immune cells to initiate reparative processes that, if unresolved, can lead to fibrosis and organ damage. The directionality of effect between fibrosis and inflammation in the lung has been a point of debate for many years. Here, we tested the hypothesis that Interleukin 11 (IL11) signaling in fibroblasts is of primary importance for pulmonary fibrosis and that this event is upstream of lung inflammation. We generated mice with loxP-flanked Il11ra1 alleles and crossed them to a Col1a2-CreERT strain to enable Il11ra1 deletion in adult fibroblasts (Il11ra1-CKO mice). Lung fibroblasts from Il11ra1-CKO mice were selectively deleted for Il11ra1 and refractory to TGFβ1 stimulation. In the mouse model of bleomycin-induced lung fibrosis, Il11ra1-CKO mice had markedly reduced pulmonary fibrosis and lesser lung damage, which was accompanied by diminished ERK activation in the stromal compartment. Bleomycin lung injury in Il11ra1-CKO mice was also associated with diminished STAT3 activation in inflammatory cells, fewer pulmonary immune cell infiltrates and almost complete inhibition of NF-kB activation. These data reveal an essential role for IL11 signaling in fibroblasts for lung fibrosis and show that inflammation in the lung can be secondary to stromal activation.
Dong Jinrui、Viswanathan Sivakumar、Widjaja Anissa A.、Paleja Bhairav S.、Lim Stella、Chothani Sonia P.、Albani Salvatore、Schafer Sebastian、Tan Jessie、Ng Benjamin、Adami Eleonora、Cook Stuart A.、Ko Nicole SJ.、Wang Mao
Duke-National University of Singapore Medical SchoolDuke-National University of Singapore Medical SchoolDuke-National University of Singapore Medical SchoolTranslational Immunology Institute, SingHealth/Duke-NUS Academic Medical CentreDuke-National University of Singapore Medical SchoolDuke-National University of Singapore Medical SchoolTranslational Immunology Institute, SingHealth/Duke-NUS Academic Medical CentreNational Heart Centre Singapore||Duke-National University of Singapore Medical SchoolNational Heart Centre Singapore||Duke-National University of Singapore Medical SchoolNational Heart Centre Singapore||Duke-National University of Singapore Medical SchoolDuke-National University of Singapore Medical SchoolNational Heart Centre Singapore||Duke-National University of Singapore Medical School||National Heart and Lung Institute, Imperial College||MRC-London Institute of Medical Sciences, Hammersmith Hospital CampusDuke-National University of Singapore Medical SchoolDuke-National University of Singapore Medical School
基础医学生物科学研究方法、生物科学研究技术生理学
Dong Jinrui,Viswanathan Sivakumar,Widjaja Anissa A.,Paleja Bhairav S.,Lim Stella,Chothani Sonia P.,Albani Salvatore,Schafer Sebastian,Tan Jessie,Ng Benjamin,Adami Eleonora,Cook Stuart A.,Ko Nicole SJ.,Wang Mao.Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/801852.点此复制
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