M2 Macrophage Research Paper

The alternatively activated43,22,55,59 M2 macrophage is anti-inflammatory44, and is characterised by a circular appearance30, low IL12 and IL23 with high IL10 as well as an increase in the expression of mannose and galactose receptors and the metabolism of arginine through arginase to ornithine and polyamine43,20,27,63,18. Arginase is known to help decrease lymphocyte proliferation1. M2 also have increased urea production, CD180, CD163, TREM2 and stabilin expression and decreased TNF-α, CD40 and CD86 expression27,29,30. M2 macrophages have various subtypes25,27,30,43,55,18,20,18. Subtype M2A is induced by Th2 responses, IL4 and IL13, M2B is induced by immune complexes and TLR and subtype M2C is induced by IL10, TGF-β and glucocorticoids25,30,55,20.

As the cytokine binds to the receptor the receptor changes conformation thus bring the JAKs closer together and facilitating transphosphorylation of each other. The JAKs are now able to phosphorylate the tyrosines present on the cytokine receptors to become phosphotyrosines and which allow STATs to attach via their SH2 domain. Once attached, JAKs phosphorylate the STATs which then dissociate from the receptor. The STATs SH2 domain now mediates the binding of phosphotyrosines on two STATs to form a dimer. Once dimerised the STATs translocate to the nucleus through the nuclear pore and stimulates the transcription of the target gene6. Target genes of STATs include suppressors of cytokine signalling molecules (SOCS) which act through negative feedback to supress further signalling60. There are also inhibitors of STATS known as protein inhibitor of activated STATS (PIAS) which prevent the binding of STATS to DNA4.
The JAK/STAT pathway is used in the polarisation of M1 and M2 macrophages. IFN-γ which is produced during the TH1 response activates JAK1 or JAK2 to dimerise STAT1 which induces the M1 macrophage phenotype59,66,8. In contrast, IL4 produced during the TH2 response activates JAK1 or JAK3 to dimerise STAT6 which then induces the M2