DDR1 activation in macrophage promotes IPF by regulating NLRP3 inflammasome and macrophage reaction
DDR1 activation in macrophage promotes IPF by regulating NLRP3 inflammasome and macrophage reaction
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巨噬细胞中DDR1激活通过调节NLRP3炎症小体和巨噬细胞反应促进IPF
DOI：
10.1016/j.intimp.2022.109294
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发表时间：
2022
影响因子：
5.6
通讯作者：
Jie Yan
中科院分区：
文献类型：
--
作者：
Hao Wang;Yuhuan Wen;Linjie Wang;Jing Wang;Honglv Chen;Jiaqian Chen;Jieying Guan;Shiyun Xie;Qile Chen;Yongta Wang;Ailin Tao;Yanhua Du;Jie Yan
Discoidin结构域受体1(DDR1)是受体酪氨酸激酶(RTK)中的一员，与特发性肺纤维化(IPF)相关，但其作用机制尚不清楚。通过慢病毒介导的DDR1-/-稳定的Raw264.7巨噬细胞系和DDR1抑制剂的体外处理，研究DDR1对炎症体活化和巨噬细胞反应的影响，并在IPF患者的肺切片上进一步验证这些机制。(2)免疫荧光染色显示DDR1信号在巨噬细胞中被激活，在活体分子生物学分析中证实DDR1的激活通过炎症小体信号、巨噬细胞激活和M1/M2极化来加重IPF的炎症。(3)细胞外基质(ECM)如胶原1在体外激活巨噬细胞系Raw264.7的DDR1，介导炎症小体激活和巨噬细胞反应。(4)在IPF患者的巨噬细胞中证实了DDR1的激活，这可能是IPF发病的机制之一。此外，DDR1抑制剂DDR1-IN-1和DDR1-IN-2在IPF中具有显著的抗炎和抗纤维化作用，为临床治疗IPF提供了一种潜在有效的治疗药物。
BackgroundDiscoidin Domain Receptor1 (DDR1) is a member of receptor tyrosine kinases (RTKs) which have been reported to be associated with idiopathic pulmonary fibrosis (IPF), but the mechanism remains unclear.MethodsBleomycin-induced IPF mice model was performed in this study, and two DDR1 inhibitors were administered in vivo, to investigate the role of DDR1 in IPF. Lentivirus mediated DDR1-/-stable Raw264.7 macrophage cell line or DDR1 inhibitors treatment in vitro, to study the effect of DDR1 on inflammasome activation and macrophage responses.All of the mechanisms were further tested in the lung sections of IPF patients.ResultHere, we reported that: (i) Both specific inhibitors of DDR1 dramatically alleviated the symptoms of bleomycin-induced IPF models. (ii) Immunofluorescence staining showed that DDR1 signaling is activated in macrophages.In vivomolecular biological analysis proved that DDR1 activation exacerbates IPF inflammation through inflammasome signaling, macrophage activation, and M1/M2 polarization. (iii) Extracellular matrix (ECM) such as Collagen 1 activates DDR1 in macrophage cell line Raw264.7 in vitro, to mediate inflammasome activation and macrophage responses. (iv) DDR1 activation in macrophage was confirmed in IPF patients’ samples, which could be one of the mechanisms for the pathogenesis of IPF.DiscussionIn this study, we firstly reported DDR1 activation in macrophages to play a role in IPF via inflammasome activation and macrophage responses. In addition, DDR1 inhibitors DDR1-IN-1 and DDR1-IN-2 exerted significant anti-inflammatory and anti-fibrotic effects in IPF, all of which provide a potentially effective therapeutic medication for clinical IPF treatment.