M-1/M-2 Macrophages and the Th1/Th2 Paradigm

Abstract

Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-γ or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-β1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-γ production, while BALB/c SCID macrophages increase TGF-β production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Production of CCL17, CCL1, chemokine (C-X-C motif) ligand-13 (CXCL13) and CXCL8 (IL-8) has been proven to be associated with an M2a, M2b, M2c and M2d monocyte activation program, respectively, and are parts of mononuclear phagocyte-mediated regulatory circuits of innate and adaptive immunity (Mills et al, 2000;Sironi et al, 2006;Martinez et al, 2008;Duluc et al, 2009;Wang et al, 2010;Zhang et al, 2010a). As shown in Figure 5c, CCL17 levels markedly increased whereas CCL1 did not show apparent change upon M-CSF þ MCP-1, LXA 4 and ANXA1 administration.…”

“…Macrophages can differentiate into two subsets, classically activated macrophages (or M1) and alternatively activated macrophages (or M2), on the basis of their ability to produce interleukin-12 (IL-12) or IL-10, respectively. M1 has potent microbicidal properties and promotes Th1 responses, whereas M2 supports Th2-associated effector functions (Mills et al, 2000;Martinez et al, 2008). M2 macrophages are further subdivided into M2a, M2b, M2c and M2d cells as elicited by different stimuli (Sironi et al, 2006;Martinez et al, 2008;Duluc et al, 2009).…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…Macrophages can differentiate from blood monocytes into two distinct subtypes, namely classically activated (M1) and alternatively activated (M2) macrophages endowed with effector or suppressive functions, respectively. 10,11 Macrophages infiltrating solid tumors (that is, tumor-associated macrophages or TAMs) share many characteristics with M2 macrophages and exert a pro-tumorigenic function in virtue of their direct or indirect (via cytokine production) immune-suppressive effects towards NK and T-cells. 12 In cancer patients, the presence of TAMs favors tumor progression.…”

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

“…The balance of NO/arginase activity is mutually regulated 14 and has been associated with 'classic' or 'alternative' MF activation. 15,16 Accordingly, we measured arginase activity and NO production in BMMF following activation with lipopolysaccharide (LPS) alone or LPS and interferon (IFN)-g in combination. Secretion of NO did not differ between R17 and DA MF (Figure 3b), but there was indeed a lower arginase activity in R17 rat MF compared with DA (1.01±0.38 vs 1.39 ± 0.46, P ¼ 0.024) (Figure 3a), suggesting differential MF activation.…”