Table 2.
Combinatorial marker systems for phenotyping activated macrophages*
| Marker type | Associated signalling molecules |
Gene (alternative names) | Comments |
|---|---|---|---|
| M2 markers | STAT6 phosphorylation in vivo and ex vivo without further perturbation | Relma (Fizz1, Retnla) | Highly induced by IL-4 and IL-13. Not expressed in humans |
| Socs2 | Highly induced by IL-4 and IL-13. Not macrophage-specific | ||
| Irf4 | Highly induced by IL-4 and IL-13. Not macrophage-specific | ||
| Chia (Amcase) | Highly induced by IL-4 and IL-13. Not macrophage-specific | ||
| Chi3l1 (Gp39, Ykl40) | Highly induced by IL-4 and IL-13. Not macrophage-specific | ||
| Chi3l2 (Ykl39) | Not expressed in mice | ||
| Chi3l3(Ym1) | Not expressed in humans. Can be highly induced by IL-4 and IL-13 in some situations | ||
| Cxcl13 | Chemokine linked to TH2 cell responses | ||
| Ccl12 | Chemokine linked to TH2 cell responses | ||
| Ccl24 | Chemokine linked to TH2 cell responses | ||
| Klf4 | Transcription factor induced by IL-4 in both mouse and human macrophages171 | ||
| M1 markers |
|
Marco | Calmodulin-associated. Also found in other activation scenarios |
| Socs3 | Induced by IL-10, IL-6 and many other factors | ||
| Nos2 | Not readily expressed in human macrophages | ||
| Il12b | Highly induced in M1 activation | ||
| Ptgs2 (Cox2) | Highly induced in M1 activation | ||
| Il23α (Il23p19) | Highly induced in M1 activation | ||
| Ido1 | Useful marker of human and mouse exposure to type 1 and 2 interferons | ||
| Context-dependent markers | Arg1 | Can be induced by the STAT6 or STAT3 pathways172,173 | |
| Il10 | Differentially produced by most, if not all macrophages174 | ||
| Mrc1 | Linked with M2 macrophages but widely expressed on many macrophage subsets |
Arg1, arginase 1; Ccl, CC-chemokine ligand; Chi3l, chitinase 3-like; Chia, chitinase, acidic; Cxcl13, CXC-chemokine ligand 13; Ido1, indoleamine 2,3-dioxygenase 1; Il, interleukin; Irf4, interferon regulatory factor 4; Klf4, Krüppel-like factor 4; Marco, macrophage receptor with collagenous structure; Mrc1, mannose receptor, C type 1; Nos2, nitric oxide synthase 2, inducible; Ptgs2, prostaglandin-endoperoxide synthase 2; Relma, resistin-like molecule alpha; Socs, suppressor of cytokine signalling; STAT, signal transducer and activator of transcription; TH2, T helper 2.
Shown are marker combinations that can be used to assign phenotypic characteristics to a mouse macrophage population. The use of multiple markers, especially when combined with assays for phosphorylated STATs, avoids the problems associated with markers, such as ARG1, that are widely expressed in either M1 or M2 polarized environments.
A notable exception is the infection of macrophages by Fransicella spp. — in this case, autocrine or paracrine IL-4 and IL-13 production is enforced by a myeloid differentiation primary response protein 88 (MYD88)-dependent pathway175, and the subsequent activation of STAT6 favours bacterial survival.