Dutta Saugata, Zhu Yin, Almuntashiri Sultan, Peh Hong Yong, Zuñiga Joaquin, Zhang Duo, Somanath Payaningal R, Ramírez Gustavo, Irineo-Moreno Valeria, Jiménez-Juárez Fabiola, López-Salinas Karen, Regino Nora, Campero Paloma, Crocker Stephen J, Owen Caroline A, Wang Xiaoyun
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia, United States.
Charlie Norwood VA Medical Center, Augusta, Georgia, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 1;328(1):L60-L74. doi: 10.1152/ajplung.00104.2024. Epub 2024 Nov 25.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs), but little is known about the role of TIMP-1 in regulating the pathogenesis of influenza A virus (IAV) infection. Here, we performed both in vivo and in vitro experiments to investigate the regulation and function of TIMP-1 during IAV infection. Specifically, plasma levels of TIMP-1 are significantly increased in human subjects and wild-type (WT) mice infected with 2009 H1N1 IAV compared with levels in uninfected controls. Also, TIMP-1 is strikingly upregulated in PDGFRα positive (PDGFRα) cells in IAV-infected murine lungs as demonstrated using conditional KO (cKO) mice with a specific deletion of in PDGFRα cells. Our in vitro data indicated that TIMP-1 is induced by transforming growth factor-β (TGF-β) during lipofibroblasts (lipoFBs)-to-myofibroblast (myoFB) transdifferentiation. deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. IAV-infected deficient mice showed increased macrophages, and B and T cell counts in bronchoalveolar lavage (BAL) on postinfection (p.i.), but reduced BAL neutrophil counts. Increased Cxcl12 levels were detected in both BAL cells and lungs from deficient mice on p.i. Taken together, our data strongly link TIMP-1 to IAV pathogenesis. We identified that PDGFRα-lineage cells are the main cellular source of elevated TIMP-1 during IAV infection. Loss of attenuates IAV-induced mortality and promotes T and B cell recruitment. Thus, TIMP-1 may be a novel therapeutic target for IAV infection. Our data strongly link tissue inhibitor of metalloproteinases-1 (TIMP-1) to influenza A virus (IAV) pathogenesis. TIMP-1 is highly increased in PDGFRα-lineage cells during IAV infection. Transforming growth factor-β (TGF-β) induces TIMP-1 during lipofibroblast (lipoFB)-to- myofibroblast (myoFB) transdifferentiation. deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. TIMP-1 may be a novel therapeutic target for IAV infection.
金属蛋白酶组织抑制剂-1（TIMP-1）是基质金属蛋白酶（MMPs）的生理性抑制剂，但关于TIMP-1在调节甲型流感病毒（IAV）感染发病机制中的作用知之甚少。在此，我们进行了体内和体外实验，以研究IAV感染期间TIMP-1的调节和功能。具体而言，与未感染的对照组相比，感染2009 H1N1 IAV的人类受试者和野生型（WT）小鼠的血浆TIMP-1水平显著升高。此外，如使用在PDGFRα细胞中特异性缺失的条件性敲除（cKO）小鼠所证明的，IAV感染的小鼠肺中PDGFRα阳性（PDGFRα）细胞中的TIMP-1显著上调。我们的体外数据表明，在脂肪成纤维细胞（lipoFBs）向肌成纤维细胞（myoFB）转分化过程中，转化生长因子-β（TGF-β）可诱导TIMP-1。 缺陷可保护小鼠免受H1N1 IAV诱导的体重减轻、死亡和肺损伤。感染IAV的缺陷小鼠在感染后（p.i.）第 天的支气管肺泡灌洗（BAL）中显示巨噬细胞、B细胞和T细胞计数增加，但BAL中性粒细胞计数减少。在感染后第 天，缺陷小鼠的BAL细胞和肺中均检测到Cxcl12水平升高。综上所述，我们的数据有力地将TIMP-1与IAV发病机制联系起来。我们确定PDGFRα谱系细胞是IAV感染期间TIMP-1升高的主要细胞来源。 的缺失可减轻IAV诱导的死亡并促进T细胞和B细胞募集。因此，TIMP-1可能是IAV感染的新型治疗靶点。我们的数据有力地将金属蛋白酶组织抑制剂-1（TIMP-1）与甲型流感病毒（IAV）发病机制联系起来。在IAV感染期间，TIMP-1在PDGFRα谱系细胞中高度增加。在脂肪成纤维细胞（lipoFB）向肌成纤维细胞（myoFB）转分化过程中，转化生长因子-β（TGF-β）诱导TIMP-1。 缺陷可保护小鼠免受H1N1 IAV诱导的体重减轻、死亡和肺损伤。TIMP-1可能是IAV感染的新型治疗靶点。
