Deficiency of the collagen endocytic receptor MRC2 accelerates mouse lung fibroblast proliferation

Mannose receptor C type 2 (MRC2) is highly expressed in the lung and is the major endocytic receptor for the internalization and degradation of collagen in mesenchymal cells. Using Mrc2 knockout (KO) mice, we previously showed that MRC2 is required for efficient clearance of collagen in bleomycin-induced fibrosis. However, MRC2 also interacts with various cell-surface receptors and ligands beyond collagens, indicating that MRC2 may have additional, previously unrecognized functions in fibroblasts. To uncover novel pathways regulated by MRC2, we took an unbiased approach to compare the transcriptomic profile of MRC2-deficient lung fibroblasts to WT after in vitro culture. RNA-seq analysis revealed upregulation of the expression of several extracellular matrix genes but unexpectedly showed changes in expression of several cell cycle genes, including that encoding Forkhead box M1 (FOXM1), a key regulator of cell cycle progression, and enrichment of pathways involved in mitosis and cell division. Both in vitro and in vivo functional assays demonstrated that a greater proportion of MRC2-deficient lung stromal cells progress through the cell cycle more rapidly than WT cells, thereby accelerating overall proliferation. Inhibitor experiments showed that actively proliferating Mrc2 KO fibroblasts are more reliant on FOXM1 activity compared with WT cells, suggesting that FOXM1 is a critical mediator in fibroblast proliferation in the absence of MRC2. Our findings point to an unexpected role for this endocytic receptor in the regulation of lung stromal cell proliferation.