Tissue-Resident Macrophages: Linking Physiology and Inflammation in Infection.

Macrophages are found in every tissue in the body, and their importance goes far beyond clearing pathogens. Developmental studies have shown that many macrophage populations originate during embryogenesis, persist through self-renewal, and adopt transcriptional and functional programs defined by their tissue environment. These tissue-resident macrophages (TRMs) are embedded within organ physiology, where they regulate, for instance, cardiac conduction, sculpt synaptic circuits, recycle iron, maintain epithelial barriers, and coordinate repair. During infection, TRMs connect to neural, metabolic, and structural circuits; therefore, inflammatory activation can alter organ function long after pathogen clearance. We propose that TRMs function as physiological integrators of immunity, translating local environmental cues into immune responses constrained by the demands of their tissue. This review examines macrophage populations across interconnected physiological systems, including the heart-brain axis, the spleen-liver network, and barrier tissues. In these settings, developmental origin, niche-derived signals, and metabolic programming determine how macrophages respond to infection and whether they preserve or disrupt tissue homeostasis. Additionally, we discuss how loss of resident identity during inflammatory stress contributes to chronic pathology and post-infectious sequelae and how emerging therapeutic strategies aim to restore tissue-specific macrophage programs. By framing immunity within organ physiology, we offer a conceptual model for understanding how infection reshapes tissue function through resident macrophages, as well as how targeting these cells could prevent long-term damage.