Targeting circulating mechanoresponsive monocytes and macrophages to reduce fibrosis
Kellen Chen, Michelle Griffin, Dominic Henn, Katharina S. Berryman, Dharshan Sivaraj, Hudson C. Kussie, Clark A. Bonham, Eamonn McKenna, Maria Gracia Mora Pinos, Abdelrahman M. Alsharif, Fidel Saenz, Nicholas Matthews, Maisam Jafri, Jonathan P. Yasmeh, Mimi R. Borrelli, Savana L. Huskins, Sydney R. Steele, Amelia B. Knochel, Mansi Singh, Andrew C. Hostler, Melissa C. Leeolou, William W. Hahn, David Perrault, Darren Abbas, Nicholas Guardino, Benjamin Thomas, Janos A. Barrera, Chikage Noishiki, Artem A. Trotsyuk, Jagannath Padmanabhan, Michael Januszyk, Mohammad Khreiss, Michael T. Longaker, G.C. Gurtner
Abstract
In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation. Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations. In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.