From support to homeostatic licensing: the bidirectional fibroblast-macrophage circuit and its central role in tissue homeostasis and fibrosis.

The capacity of fibroblasts to support macrophages predominantly through colony-stimulating factor 1 (CSF1)-mediated survival and proliferation has long been recognized. Whether macrophages actively regulate fibroblasts in vivo has remained a critical open question. Recent work in murine skin has provided the first direct evidence for reverse homeostatic licensing, a process whereby macrophages, in return, provide permissive signals that maintain fibroblast quiescence: conditional deletion of Csf1 in dermatopontin-expressing (Dpt+) fibroblasts causes a progressive loss of CD64+ and CD11c+ macrophages, which in turn deprives fibroblasts of essential microenvironmental cues, leading to disrupted cell-cycle, metabolic, and immune signaling programs, and compensatory fibroblast expansion. This discovery formally defines a bidirectional circuit. In human systemic sclerosis, elevated fibroblast-derived CSF1 and increased macrophage abundance jointly correlate with disease severity, a paradox we resolve through the concept of functional licensing exhaustion in disease-associated macrophages. Taking this breakthrough as a point of departure, we integrate the concept of a fibroblast-macrophage homeostatic circuit as a generalizable framework. We examine how this push-pull loop operates in tissue maintenance, wound repair, and fibrogenesis; explore its similarities and divergences in the tumor microenvironment and across organ fibroses; and propose a therapeutic shift from simple cell depletion to the restoration of circuit equilibrium. The framework provides a conceptual basis for clinical strategies that target stromal-immune interactions.