Immune–Vascular intercellular signalling coordinates tissue plasticity during adult muscle repair in Drosophila

In skeletal muscle, immune and vascular responses are essential for regeneration, yet the cellular and molecular mechanisms that coordinate their activities to restore tissue function remain unclear. Here, using Drosophila, we uncover a multi-organ signaling program that integrates muscle fibers, macrophages, vascular-like tracheal cells, and the extracellular matrix (ECM) to drive adult skeletal muscle repair. Muscle injury induces rapid macrophage recruitment and secretion of the FGF-like ligand Branchless (Bnl), which activates FGF/FGFR signalling in tracheal cells and promotes their targeted expansion toward damaged muscle. Concomitantly, macrophages deposit ECM components on the damaged muscle, including Collagen IV, forming a localized microenvironment that restricts Bnl ligand diffusion and facilitates directed tracheal remodelling. Genetic disruption of macrophage-derived Bnl or macrophage-mediated ECM deposition abolishes tracheal remodeling and compromises muscle recovery. Together, these findings reveal a previously unrecognized immune muscle vascular program in which macrophages coordinate growth factor signalling and ECM organization to shape muscle microenvironment and preserve muscle function following acute damage.