Upregulated MARCKS reprograms macrophages to drive pulmonary fibrosis progression 3890

Abstract Description Macrophages play a critical role in idiopathic pulmonary fibrosis (IPF) and are promising therapeutic targets; however, strategies targeting macrophage polarization in IPF have yielded limited success. Our single-cell transcriptomic analysis reveals that alveolar macrophages in IPF lung tissues exhibit enhanced fibrosis-related transcriptional signatures. Notably, the multifunctional molecule myristoylated alanine-rich C-kinase substrate (MARCKS) is highly expressed and activated. IL-4 stimulation of MARCKS-proficient macrophages induces phosphorylation, aberrant survival signaling, and pathogenic phenotypes, including increased podosome formation, migration, proliferation, and expression of pro-fibrotic markers. In precision-cut lung slices, macrophage-specific MARCKS-knockout (Marcks cKO) mice displayed reduced fibroblastic foci, collagen deposition, and pro-fibrotic macrophages following fibrosis-inducing stimuli. Similarly, in a bleomycin model, while early responses were comparable between Marcks cKO and wild-type mice, Marcks cKO mice demonstrated significantly less macrophage-driven fibrosis and pathogenic macrophage presence during the later stages of fibrosis. These findings highlight the pivotal role of MARCKS and its phosphorylation in promoting progressive fibrosis through macrophage reprogramming and pro-fibrotic phenotypes. Targeting MARCKS represents a promising therapeutic approach to mitigating pulmonary fibrosis. Funding Sources This work was supported by the NIH grant R01HL146802, the UCOP TRDRP grant T32IR5347, and the DoD PRMRP grant W81XWH2110086 (#PR202411). Topic Categories Immune Mechanisms of Human Disease (HUM)