Abstract
Activation of the immune response is a critical early event during injury that determines the outcome of tissue restoration towards regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. In this study we have demonstrated that during skin repair in mice interleukin-4 receptor a (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly, and that this process was important for effective repair while having adverse pro-fibrotic effects. We could show that in mice with myeloid cell-restricted IL-4Rα-deficiency (Il4raMKO) skin repair was associated with delayed wound closure, massive hemorrhages in the granulation tissue, and disturbances in extracellular matrix architecture. Ultrastructural analysis of wound tissue in Il4raMKO mice revealed an abnormal collagen fibril assembly. Intriguingly, HPLC-based analysis of the granulation tissue revealed an altered collagen cross-link pattern when compared to control mice. Whereas granulation tissue in control mice was characterized by dihydroxy lysinonorleucine (DHLNL) collagen cross-links, a typical feature of fibrotic tissue, these crosslinks were significantly reduced in Il4raMKO mice. Interestingly, wound macrophages in Il4raMKO mice revealed significantly reduced expression of Relm-a, a small cysteine-rich secreted molecule that is a hallmark of alternatively activated macrophages and has been associated with experimental fibrosis and pro-fibrotic conditions in human diseases. By using an in vitro macrophage-fibroblast co-culture system we identified Relm-a released from macrophages as inducer of lysyl hydroxylase 2 (LH2) expression in fibroblasts. LH2 is known to play a pivotal role directing DHLNL collagen cross-links. Collectively, our findings provide novel mechanistic insights in the link between type 2 immunity and initiation of pro-fibrotic pathways, and offer interesting perspectives for therapeutic innovation.
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have