This review examines how TGF-β shapes the identity and function of tissue-resident macrophages (microglia, Langerhans cells, alveolar macrophages, intestinal macrophages, sensory nerve-associated macrophages, and interstitial macrophages) across distinct organ niches, focusing on the spatial and temporal regulation of TGF-β activation rather than its overall abundance.
TGF-β acts as a niche-specific, contact-dependent determinant of macrophage identity: its localized activation via integrins (αvβ6, αvβ8, αvβ5) and anchor molecules (LRRC33, GARP) drives tissue-specific transcriptional programs (e.g., SMAD–SALL1 in microglia, RUNX3/Id2 in Langerhans cells, PPAR-γ in alveolar macrophages). Loss of TGF-β signaling in conditional knockout models consistently causes loss of macrophage identity markers, reduced cell numbers, and impaired tissue homeostasis across all studied populations.
This is a narrative review with no original experimental data; causality is inferred from mouse genetic models that may not fully translate to humans. Species-specific differences in integrin expression (e.g., αvβ8 on human vs. murine intestinal macrophages) limit direct extrapolation. The cellular sources of TGF-β and its precise spatial availability remain undefined for most macrophage subsets.
Systemic TGF-β inhibition carries significant risks (cardiovascular toxicity, immune dysregulation); spatially restricted strategies—such as targeting integrin αvβ8 or using nanoparticles to deliver TGF-β1 siRNA selectively to CD206+ macrophages—show more promise for fibrosis and cancer with reduced off-target effects. Clinicians should recognize that macrophage-TGF-β biology is highly context-dependent, and broad anti-TGF-β approaches are unlikely to be sufficient or safe.
