Tissue-resident macrophages
Nat Immunol.(IF30.5), 2013 October ; DOI: 14(10): 986–995. doi:10.1038/ni.2705.
组织驻留细胞marker: CX3CR1,CSF1R

1. 组织巨噬细胞功能在于维持细胞稳态环境、免疫监测、细胞碎片处理、炎症消除等

These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune-surveillance, response to infection and the resolution of inflammation

2. 组织驻留细胞来源于造血干细胞单核细胞补充，或胚胎时期生成的巨噬细胞的自我更新

the origins of tissue macrophages that arise from hematopoietic versus selfrenewing embryo-derived populations.

3. 多个组织中存在组织特异有别于单核来源巨噬的细胞，例如skin (Langerhans cell), liver (Kupffer cell), brain (microglia), pancreas, lung and spleen (red pulp macrophage) and kidney，这些细胞作为胚胎来源巨噬的组织驻留巨噬细胞证据。且研究发现皮肤中的朗格汉斯细胞和大脑中的小胶质细胞具有自我增殖的特征。

One study showed Langerhans cells in adult mice are created by the local expansion of Langerhans cells in the neonate14. Brain microglia also renew themselves via local proliferation.

4. 研究表明CSF1R对胎儿时期巨噬细胞的形成和自我更新有关键性作用，可作为组织驻留巨噬细胞marker

Intriguingly, while all of the defects of the op mouse were evident in mice deficient in its receptor CSF1R, there were notable differences; principally the additional loss of Langerhans cells and microglia in Csf1r-deficient mice, which were overtly normal in the op mouse. These tissue-specific ‘anomalies’ were explained by the alternate CSF1R ligand, interleukin 34 (IL-34). IL-34 was found to be selectively produced by keratinocytes and neurons, accounting for the defects in the prenatally derived Langerhans cells and microglia, respectively18, 19. Intriguingly, IL-34 and M-CSF are expressed in different locations in the brain, suggesting the possibility of distinct outcomes of CSF1R activation by these ligands.

5. 轻度腹膜炎情况下的巨噬细胞定量中，主要是中性粒细胞急剧增加维持炎症反应一天后，单核来源巨噬细胞开始占据主导地位。

We have quantified macrophage subsets in mild zymosan peritonitis. In this model, we observe an acute neutrophilic influx, which is resolved in a day, followed by a prolonged retention of inflammatory monocyte-derived macrophages within the lesion

6. 组织驻留细胞在组织修复，伤口愈合方面有关键性作用，尽管具体细节和作用还不清晰。

Thus the contribution of tissueresident cells has largely been neglected. Nonetheless, the importance of macrophages in wound healing is underscored by time-dependent conditional depletion of macrophages in mice. Depletion in the inflammatory phase demonstrated roles for macrophages in the formation of vascularized granulation tissue, epithelialization and minimizing scar formation. Depletion during the tissue formation stage led to hemorrhage and a failure of wound closure

7. 死亡细胞的清理策略涵盖了单核来源的巨噬细胞和组织驻留巨噬细胞，单核来源巨噬细胞吞噬大量的死亡细胞，而组织驻留细胞不依赖于MFG-E8的细胞清理，对细胞清理更加精确。

However, even though inflammatory monocyte-derived macrophages are less efficient they greatly outnumber resident cells in many inflammatory contexts, and will likely still phagocytose a substantial number of apoptotic cells. Such fundamental processes are unlikely to be controlled by a single regulatory mechanism, especially considering the diversity of apoptotic cell recognition systems that have been described

8. 死亡细胞受体：Mertk, Axl, and Tyro3 Macro/DC高表达，组织驻留细胞更倾向于表达MERTK

Macrophages and dendritic cells are proposed to differentially express the apoptotic cell receptors Mertk, Axl and Tyro3 (ref. 84), which may further regulate these clearance processes. To exemplify, Mertk, a receptor preferentially expressed by tissue-resident macrophages33, has an increasingly well-defined role in apoptotic cell clearance and the prevention of autoimmunity

9. 组织驻留巨噬细胞的主要功能可能是助力于组织稳态的维持。

Some of the most critical roles of tissue-resident macrophages may prove to be in energy homeostasis.

不同组织下的组织驻留巨噬细胞：
Tissue aCell type bFunctions & notes Phenotypic markers
(cTissue-selective transcriptional regulators)
Adipose tissue ‘Adipose-associated macrophages’ Involved in control of insulin sensitivity96 and adaptive thermogenesis99. F4/80+, CD45+ (white and brown adipose tissue)99 (PPARγ96)
Blood Ly-6Clo monocytes These monocytes function analogously as “intravascular housekeepers” clearing endothelial cell debris115.
CX3CR1+, Ly-6Clo, F4/80+, CSF1R+ 115 (Nr4a1115)
Bone Osteoclasts Multinucleated cells formed by fusion that resorb bone by disruption of the mineralized matrix36.Calcitonin receptor+ (multinucleate)117 Bone marrow macrophages Supporting erythropoeisis87, 88. Maintenance of hematopoietic stem cells in stem cell niches116. An independent self-renewing population30. CD169+, F4/80+, ER-HR3+ 118
Central nervous system Microglia Promotes neuronal survival, front-line immune-surveillance cell, removal of dead neurons, synaptic remodelling76, 119. Derived from yolk sac and maintained and during inflammation independently of the bone marrow 15, 26, 65. F4/80+, CD11b+, CD45lo 120 Perivascular macrophages Immune surveillance. F4/80+, CD11b+, CD163+, CD45hi 120 Meningeal macrophages Immune surveillance120. F4/80+, CD11b+, CD45hi 120
Gastrointestinal tract Intestinal macrophages Maintenance of intestinal homeostasis and regulation of immune responses to commensals23, 121. CX3CR1hi, F4/80+, CD11b+, CD11c+, CD64+ 121
Liver Kupffer cells (sessile) Clearance of microorganisms and cell debris from the blood. Clearance of aged erythrocytes91, 122. Pre-natal origins22. Maintained in the adult independently of the bone marrow17 F4/80hi, CD11blo, CD169+, CD68+, Galectin-3+123,dCD80lo/− 122 (PPARδ98) Motile liver macrophages Immune surveilance122 F4/80+, CD11b+, CD80hi 122
Lung Alveolar macrophages Immune-surveillance of the lung for inhaled pathogens51, homeostatic regulation of tissue function72, 124, for example clearance of surfactant. Prenatal origins22. Maintained in adult and during inflammation independently of the bone marrow30, 125.
F4/80lo, CD11blo, CD11chi, CD68+, Siglec F+, MARCO+, CD206+, Dectin-1+127, Galectin-3+ 123 (PPARγ72) Interstitial macrophages Regulates DC maturation/activation126. F4/80+, CD11c−, CD68+, MHCII+ 126
Serosal tissues Peritoneal macrophages: F4/80hi majority Immune surveillance and regulation of homeostatic environment50, 128. Apoptotic cell clearance80. Pre-natal origins22. Maintained in adult and during inflammation independently of the bone marrow22, 29. F4/80hi, CD11bhi, dTim4+ 83 MHCIIlo F4/80lo Pleural macrophages: Immune surveillance129. F4/80lo, CD11b+, Tim4−, MHCIIhi, CD11c+/− (This population is most likely heterogeneous, mixed with dendritic cells) F4/80hi majority Maintained in adult and can expand during TH2 inflammation independently of the bone marrow41 F4/80hi, CD11bhi, dTim4+ F4/80lo F4/80lo, CD11b+, Tim4− (Dendritic cell-macrophage content undetermined, unpublished phenotypic observations)
Skin Dermal macrophages Immune surveillance130. F4/80+, CD11b+, CD11clo, CD206+, MHCIIlo, CD169+ (In the deep dermis)123, Dectin-1+, CD301+ 132, Dectin-2+ 133 Langerhans cells Interaction with T lymphocytes131. Derived from yolk sac and/or fetal liver and maintained independently of the bone marrow14, 16. F4/80+, CD11b+, CD11c+, Langerin+ 14 (Id2134, Runx3135)
Spleen Marginal zone macrophages Immune surveillance of the circulation102. CD68+, CD209b+, MARCO+, Dectin-2+ 133, Tim4+ 109.
(LXRα109) Metallophilic macrophages Immune surveillance102. CD68+, CD169+ 102 (LXRα109) Red-pulp macrophages Erythrocyte clearance and iron metabolism103. Pre-natal origins17, 22. Maintained in adult independently of the bone marrow30. F4/80+, CD206+, Dectin-2+ 133 (Spi-C103) White pulp (tingible body) macrophages Clearance of apoptotic cells resulting during the germinal center reaction100. CD68+ 102 a