M2 macrophages (CD68+ CD163+)

M2 phenotypes can be replaced with M(Interleukin-4 (IL-4) + Interleukin-13 (IL-13)) or according to the stimulation by cytokines [like M(IL-4) or M(IL-10), etc.].
Parmar et al. 2020 J Immunol 204: 2762

M2 macrophages (CD68+ CD163+) exhibit tissue remodeling and repair functions, promote wound healing , angiogenesis , and resistance to Parasites / Parasitism , and favor Tumor growth

However, the molecular pathways that govern their differentiation have remained incompletely understood.

Byers & Holtzman 2011 Chest 140(3): 768-774
Belizario et al. 2018
Faas et al. 2021 Immunity 54: 2531-2546

• Phenotypic markers: CD68+, CD163+


• Transcription factors: Signal transducer and activator of transcription 3 (STAT3), Cyclic AMP-dependent transcription factor ATF-3 (ATF3), Glucocorticoid receptor (GR)


• Inducing stimuli: Interleukin-4, Interleukin-13


• Secreted factors: Interleukin-10, Arginase, TGF beta

Murray et al. 2014 Immunity 41: 14-20
Bashir et al. 2016 Inflamm. Res. 65: 1-11
Wynn & Vannella 2016 Immunity 44(3): 450-462
Belizario et al. 2018

M2 phenotype is triggered by CD4+ Th2 Cells & Cytokines such as interleukin-4 and interleukin-13 as well as anti-inflammatory cytokines , Interleukin-10 (IL-10) and Transforming growth factor beta (TGF-beta), or glucocorticoids

Hoppstädter et al., 2015
Belizario et al. 2018

The M2 type is characterized by expression of arginase-1 , YM-1, Fizz-1, mannose receptors , scavenger receptors and chemokine genes, such as ccl1 gene , ccl17 gene , ccl22 gene , ccl16 gene , ccl18 gene and ccl24 gene

Mantovani et al. 2004 Trends Immunol. 25: 677-686

M2-like genes are arg1 gene, cd163 gene, MRC1, and vegfa gene.

Azizi et al. 2018 Cell 174(5): 1293–1308

In M2 macrophages (CD68+ CD163+) the tricarboxylic acid (TCA) cycle is intact and participates in oxidative phosphorylation, providing ATP for energy.

Jha et al. 2015 Immunity 42: 419-430
O’Neill et al. 2016

This allows the generation of UDP-GlcNAc intermediates that are necessary for the glycosylation of M2-associated receptors, such as the mannose receptor .

Jha et al. 2015 Immunity 42: 419-430

The inhibition of HIF1alfa (e.g., by hypoxia, danger signals) will change the phenotype of the macrophage from a pro-inflammatory M1 phenotype to a pro-reparatory (or alternatively activated) M2 phenotype.

O’Neill et al. 2016

Activation of their differentiation from the classic M1 macrophage phenotype is typically mediated by interleukin-4 (IL-4) and interleukin-13 (IL-13)

Byers & Holtzman 2011 Chest 140(3): 768-774

see also:
Glycolysis & Macrophage polarization
THP-1 cell line
Tumor-Associated Macrophages (TAM)