PDGFRα-positive cell-derived TIMP-1 modulates adaptive immune responses to influenza A viral infection

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 328; no. 1; pp. L60 - L74
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2025
• Subjects: Adaptive Immunity; Animals; Bronchus; Clonal deletion; CXCL12 protein; Female; Growth factors; Humans; Immune response; In vivo methods and tests; Infections; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - immunology; Influenza, Human - immunology; Lavage; Leukocytes (neutrophilic); Lung - immunology; Lung - metabolism; Lung - pathology; Lung - virology; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Male; Matrix metalloproteinase; Matrix metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Myofibroblasts - immunology; Myofibroblasts - metabolism; Myofibroblasts - pathology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Pathogenesis; Physiology; Plasma levels; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Therapeutic targets; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Weight loss; lipofibroblast; PDGFRα; CXCL12; myofibroblast; adaptive immunity
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00104.2024

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. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. TIMP-1 may be a novel therapeutic target for IAV infection. 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 Timp-1 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. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. IAV-infected Timp-1-deficient mice showed increased macrophages, and B and T cell counts in bronchoalveolar lavage (BAL) on day 7 postinfection (p.i.), but reduced BAL neutrophil counts. Increased Cxcl12 levels were detected in both BAL cells and lungs from Timp-1-deficient mice on day 3 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 Timp-1 attenuates IAV-induced mortality and promotes T and B cell recruitment. Thus, TIMP-1 may be a novel therapeutic target for IAV infection. NEW & NOTEWORTHY 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. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. TIMP-1 may be a novel therapeutic target for IAV infection.