A review on the biology and properties of adipose tissue macrophages involved in adipose tissue physiological and pathophysiological processes

Table 1 Summary of ATMs phenotypes with potential functions in adipose tissues

	Stimulus	transcription factors	Cell surface markers	Cytokines	Functions
MMe macrophages	High levels of glucose, insulin, and palmitate [37]	p62 PPARγ [37]	ABCA1 CD36 PLIN2 [37]	IL-6 (NOX2-dependent) [38]	Removing dead adipocyte debris [37, 39]
CD9 macrophages		AP-1 subunit JunB NF-κB subunit p65	CD9 CD16 CD206	IL-1α IL-18 TNF	Filled with lipids, and secret exosomes [40]
Ly6c macrophages		CTCF [40, 41]	CD11b Ly6c	Factors that support vascular development and organization	Regulating adipogenesis process
MFe^hi macrophages	High iron		CD163 Tfrc Hmox1 ferritin light and heavy chains (Ftl1 and Fth1, respectively) ceruloplasmin(Cp) ferroportin-1(Slc40a1)	IL-10	Iron regulation [42, 43]
Antioxidant macrophages (Mox)			• CX3CR1^neg F4/80^loHO1⁺Txnrd1 [44]		Predominant ATMs phenotype in lean adipose tissue. Response to oxidized phospholipids (OxPLs) by upregulating Nrf2-dependent antioxidant enzymes [45]. Antioxidant macrophages (Mox) require suppression of regular energy metabolism to produce the antioxidant glutathione [46].
Hybrid M1/M2 macrophages			• CD11c⁺CD206⁺ [47] • F4/80^hiCD11c⁺CD206⁺ [44]		ATMs phenotype isolated from obese mice [44].
Macrophages in human visceral adipose			• CD14⁺CD16⁺CD36^high [48] • CD14⁺CD16⁻CD163⁺		Proinflammatory macrophages Anti-inflammatory macrophages

Macrophages with different phenotypes perform diverse functions in adipose tissue. MMe macrophages are driven by high levels of glucose, insulin, and palmitate through the p62 and PPARγ pathways, with surface markers such as ABCA1, CD36 and PLIN2. MMe macrophages secrete cytokines such as IL-6 (NOX2-dependent), performing functions that remove dead adipocyte debris. CD9 macrophages are driven through the AP-1 subunit, JunB, NF-κB and subunit p65 pathways, possess the surface markers CD9, CD16 and CD206, and secrete cytokines such as IL-1α, IL-18 and TNF. Ly6c macrophages are driven through the CTCF pathway, with their cell surface markers CD11b and Ly6c. Ly6c macrophages perform functions that regulate the adipogenesis process. MFe^hi macrophages are driven by high iron, express CD163, Tfrc, Hmox1, ferritin light and heavy chains (Ftl1 and Fth1, respectively), ceruloplasmin (Cp) and ferroportin-1 (Slc40a1). The cell surface markers of antioxidant macrophages (Mox) are CX3CR1^neg and F4/80^loHO1⁺Txnrd1. They are predominant ATM phenotypes in lean adipose tissue and respond to oxidized phospholipids (OxPLs) by upregulating Nrf2-dependent antioxidant enzymes. The cell surface markers of hybrid M1/M2 macrophages are F4/80^hiCD11c⁺CD206⁺. The cell surface markers of macrophages in human visceral adipose are CD14⁺CD16⁺CD163^high and CD14⁺CD16⁻CD163⁺