Inflammatory monocyte recruitment depends on adventitial fibroblast-derived CCL2 following influenza A virus infection 2260912

Abstract

Abstract Introduction Immune-mediated tissue damage is the major driver of severe disease after respiratory viral infections. Lung fibroblasts are emerging as central regulators of immune responses in the lungs after respiratory viral infection and have been shown to contribute to immunopathology. Recent studies have identified diverse fibroblast lineages residing in distinct lung compartments. Adventitial and peribronchial fibroblasts are located near blood vessels and larger airways in the proximal lung, and alveolar fibroblasts reside in the distal alveoli. The functional responses of these lineages and their crosstalk with immune cells during influenza A virus infections are still unclear. Methods We performed in-vitro cytokine and BAL fluid stimulations in primary fibroblast lineages, and in-vivo influenza A virus infections and determined fibroblast activation using flow cytometry. Results Our in-vitro and in-vivo experiments showed that inflammatory pathways, including IFNα and NFkêžµ signaling were preferentially activated in adventitial fibroblasts compared to alveolar or peribronchial fibroblasts. Our in-vitro experiments further demonstrated that this inflammatory activation was in part intrinsically programmed in these cells and were independent of culture conditions. Using reporter mice, we found that C-C motif chemokine ligand 2 (CCL2), a chemokine required for monocyte recruitment, was primarily expressed by adventitial fibroblasts at 6 days post-infection. Fibroblast-specific knockout of CCL2 in mice significantly reduced CCL2 levels in the blood and respiratory tract and resulted in a profound reduction in the number of monocytes recruited to the lung during infection compared to the wild type controls. Conclusion These findings identified adventitial fibroblasts as a key cell type involved in regulating early monocyte recruitment to the lung through chemokine production and highlight lung fibroblasts as a potential therapeutic target to modulate immunopathology following respiratory viral infection. Funding Source Supported by National Heart, Lung, and Blood Institute (NHLBI) - R01HL170121 , California Institute for Regenerative Medicine (CIRM) Predoctoral Fellowship - EDUC4-12759 Topic Categories Viral Immunology (VIR)