Role of Human Macrophage Polarization in Inflammation during Infectious Diseases

Abstract

Experimental models have often been at the origin of immunological paradigms such as the M1/M2 dichotomy following macrophage polarization. However, this clear dichotomy in animal models is not as obvious in humans, and the separating line between M1-like and M2-like macrophages is rather represented by a continuum, where boundaries are still unclear. Indeed, human infectious diseases, are characterized by either a back and forth or often a mixed profile between the pro-inflammatory microenvironment (dominated by interleukin (IL)-1β, IL-6, IL-12, IL-23 and Tumor Necrosis Factor (TNF)-α cytokines) and tissue injury driven by classically activated macrophages (M1-like) and wound healing driven by alternatively activated macrophages (M2-like) in an anti-inflammatory environment (dominated by IL-10, Transforming growth factor (TGF)-β, chemokine ligand (CCL)1, CCL2, CCL17, CCL18, and CCL22). This review brews the complexity of the situation during infectious diseases by stressing on this continuum between M1-like and M2-like extremes. We first discuss the basic biology of macrophage polarization, function, and role in the inflammatory process and its resolution. Secondly, we discuss the relevance of the macrophage polarization continuum during infectious and neglected diseases, and the possibility to interfere with such activation states as a promising therapeutic strategy in the treatment of such diseases.

Keywords: M1-like/M2-like; human macrophage; infectious diseases; inflammation; leishmaniasis; polarization.

Figure 1

Summary of the main macrophage polarization states of activated macrophages. Different stimuli and signaling pathways have been described as inducers of M1-like or M2-like activation states, of which the most widely referenced ones are summarized here. M1-like or M2-like polarization has been reported in humans as being related to distinct defensive or healing schemas. Many roles have been ascribed to these polarization status, of which pro- and anti-inflammatory macrophage potentiation has for a long time been classically associated to the M1-like/M2-like-like dichotomy. LPS: lipopolysaccharide; MR: mannose receptor; TNF: tumor necrosis factor; IFNg: interferon gamma; IL: interleukin; MCP: monocyte chemoattractant protein; TGF: transforming growth factor; MCSF: macrophage colony stimulating-factor; ROS: reactive oxygen species; iNOS: inducible nitric oxide synthase; MHC: major histocompatibility complex.

Figure 2

Macrophage polarization status observed in post-kala-azar dermal leishmaniasis (PKDL) patients during acute disease and after treatment. Leishmania infection in humans has been studied in PKDL patients, in which features of M2-like polarization have been observed in both lesion sites and peripheral blood. M2-like polarization is characterized by the increased mRNA and/or protein expression of specific M2-like markers such as the nuclear peroxisome proliferator activated receptor γ (PPARγ), the arginase-1 receptor, and the membrane mannose receptor CD206/mannose receptor (MR). After treatment, disease resolution is characterized by an M1-like profile repolarization, evidenced by the decreased expression of M2-like markers.