Tissue-specific macrophages: how they develop and choreograph tissue biology

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TL;DR

This review summarizes the developmental origins and functional diversity of tissue-resident macrophages, highlighting that most arise from fetal progenitors and self-renew locally, while monocyte-derived macrophages contribute variably across tissues. Macrophages orchestrate fundamental physiological processes beyond immunity, including organ development, metabolism, and neuronal function, and their dysfunction is linked to autoimmune and chronic inflammatory diseases. Understanding macrophage ontogeny and niche-specific functions is crucial for developing targeted therapies for tissue-specific pathologies.

Full summary

4,778 CHARS

**Background:** Macrophages are innate immune cells that form a 3D network in all tissues, where they phagocytose dying cells, debris, and pathogens, and produce growth factors and signaling molecules. Historically viewed as a homogeneous population derived from bone-marrow hematopoietic stem cells (HSCs), recent fate-mapping studies have revealed that most tissue-resident macrophages arise from yolk sac erythro-myeloid progenitors (EMPs) during embryogenesis and self-renew locally, with minimal HSC input during homeostasis. This review synthesizes current knowledge on macrophage ontogeny, heterogeneity, and core functions across tissues, emphasizing their roles in organ development, homeostasis, and immunity.

**Methods:** The authors conducted a narrative review of the literature, focusing on studies using fate-mapping mouse models (e.g., *Runx1*^*CreERT*^, *Cx3cr1*^*Cre*^, *Csf1r*^*MeriCreMer*^, *Flt3*^*Cre*^, *Ms4a3*^*Cre*^, *Ccr2*^*CreER*^) and single-cell transcriptomics to track macrophage development and function. They discuss key findings from studies of central nervous system (CNS), bone marrow, liver, lung, gut, skin, and oral mucosa macrophages, as well as conserved core functions and subtissular niches.

**Key Results:** - **CNS macrophages:** Microglia are entirely EMP-derived, with no HSC contribution during steady state. CNS-associated macrophages (CAMs) are also mostly EMP-derived, though ventricular macrophages show mixed ontogeny. Microglia rely on CSF1R ligands (CSF1 and IL-34) for maintenance and perform synaptic pruning, vessel guidance, and oligodendrogenesis during development. - **Bone-marrow macrophages:** Osteoclasts are long-lived, multinucleated cells that develop from EMPs and integrate HSC-derived monocyte nuclei throughout life (acquiring approximately one nucleus every 8 weeks). Erythroblastic island macrophages and osteomacs have less clear ontogeny. - **Liver macrophages:** Kupffer cells are EMP-derived and line sinusoids, clearing debris and mediating iron and cholesterol metabolism. Liver capsular macrophages are mostly monocyte-derived, with ~30% contribution from monocytes per *Ms4a3*^*Cre*^ fate mapping. Central vein and lipid-associated macrophages are newly identified populations with unknown ontogeny. - **Lung macrophages:** Alveolar macrophages are EMP-derived, self-renew, and depend on GM-CSF from type II airway epithelial cells. Interstitial macrophages include LYVE1^high^MHCII^low^ (vessel-associated) and LYVE1^low^MHCII^high^ (nerve-associated) subsets, with debated ontogeny and dependence on CSF1R signaling. - **Gut macrophages:** Lamina propria macrophages are initially fetal-derived but rapidly replaced by short-lived monocyte-derived macrophages in a CCR2-dependent manner. Long-lived TIM4^+^ subsets exist. Muscularis macrophages interact with nerves and vessels, supporting intestinal motility and neuronal survival. - **Skin and oral mucosa macrophages:** Langerhans cells are EMP-derived, long-lived, and self-renew in the epidermis. Oral mucosa Langerhans cells are of mixed origin, with postnatal replacement by preDC- and monocyte-derived cells. Dermal macrophages include vessel-associated (CX3CR1^low^LYVE1^high^MHCII^low^) and sensory-nerve-associated (CX3CR1^high^LYVE1^low^MHCII^high^) subsets, with variable monocyte contribution. - **Conserved core functions:** Macrophages share a core transcriptional program including efferocytosis (*Timd4*, *Mertk*, *Sirpa*), phagocytosis (*Cd14*, *Cd36*, *Clec7a*), and complement (*C1qb*, *C1qc*, *C3ar1*). Subtissular niches (e.g., fibroblast–macrophage circuits, vessel- and nerve-associated niches) dictate functional specialization. Macrophage core functions include metabolic regulation, blood vessel integrity, neuronal support, and stem cell maintenance. - **Autoimmunity:** Reduced phagocytic capacity or inhibitory receptor (FcγRIIb) expression is linked to systemic lupus erythematosus and rheumatoid arthritis. Synovial lining macrophages (TREM2^+^) prevent sterile inflammation in joints.

**Clinical Implications:** Understanding macrophage ontogeny and niche-specific functions is critical for developing therapies targeting tissue-specific pathologies. For example, GM-CSF deficiency causes pulmonary alveolar proteinosis, and IL-10 receptor mutations lead to severe inflammatory bowel disease. Macrophage dysfunction contributes to chronic inflammatory diseases (e.g., fibrosis, obesity) and autoimmune conditions. Future studies should address how EMP-derived versus HSC-derived macrophages differentially respond to signals and how ageing alters macrophage maintenance and function. The use of wild-type microbiota models and maternal immune activation models may improve translatability to human biology.