MCPIP: a key player in macrophage polarization

Metchinikoff’s recognition that macrophages from infected animals had elevated bacterial killing ability 120 years ago laid the foundation for the concept of macrophage activation. Interferon γ (IFNγ) produced by lymphocytes was identified as the first factor that activated resting macrophages to enhance phagocytic activity and production of proinflammatory cytokines. This state became known as the classically activated state (M1). Later, IL-4 produced by Th2 cells was found to inhibit INFγ-induced respiratory burst and enhance the expression of MHC-II suggesting a special activation state of macrophages that became known as M2 state [1, 2]. M1 macrophages produce numerous proinflammatory mediators including TNFα, IL-1, IL-6, reactive oxygen and nitrogen species implying strong bactericidal and tumoricidal activities. M2 macrophages express their own characteristic molecules such as resirtin-like-a (Fizz1), Arginase 1 (Arg1), Chitinase 3-like (Ym1), IL-10 and Mrc1(CD206) that play a role in parasitic infestation, tumor progression, tissue remodeling, angiogenesis etc. It is recognized that M1 and M2 represent two extreme states of polarization but in reality activated states of macrophages represent a full spectrum with M1 and M2 being the two extremes. Macrophage polarization state depends on their microenvironment that provides the cues for reversible states of activation. The plastic gene expression profile of macrophages is influenced by the type of stimulating agent in the microenvironment, its concentration and duration of exposure to the stimulant. The gene expressions plasticity is critically important for the adaptive response of macrophages as they migrate to different microenvironments in response to chemotactic agents and perform their functions [3]. The plethora of environmental cues that determine the macrophage activation state include cytokines, chemokines, hormones, TLR ligands, endogenous ligands such as integrin ligands, PPAR ligands etc. When the microenvironmental signals disappear macrophages revert back to the original state. Thus in vitro it can be demonstrated that when agents such as LPS that promotes M1 state or IL-4 that induce M2 state are removed the macrophages revert to the original state even though it is known that tissue specific signals may control the development of tissue specific macrophage phenotypes. In recent years considerable progress has been made in our understanding of how the microenvironmental signals cause macrophage polarization. LPS and IFNα-induced M1 polarization and IL-4-induced M2 polarizations have been studied extensively. TLR activation by LPS leads to NFkB activation that regulate production of inflammatory cytokines characteristic of M1 macrophages. M2 polarization is involved in resolution of inflammation. Stimulation of IFNα receptor triggers JAKmediated tyrosine phosphorylation leading to dimerization of STAT-1 that binds to promoters of genes encoding NOS2, the MHC II transactivator and IL-12 leading to the production of the M1 markers. Il-4 binds to its receptor IL-4Ra to cause phosphorylation of STAT6 to activate the JAK-STAT6 pathway to cause transcriptional activation of genes such as PPARγ. PPARγ regulates fatty acid metabolism promoting aerobic respiration in M2 macrophages. Many of the M2 markers in the mouse are induced by STAT6 including Arg1, Mrc1, Fizz1 and Ym1. It has been demonstrated that STAT6 and KLF4 induce each other and function cooperatively to induce M2 polarization [4]. How the transcription factors STAT6/KLF4 induce the biological processes that are necessary for IL-4induced M2 polarization was only recently elucidated. A protein that plays a central role in this M2 polarization was identified as the first member of a novel class of zinc finger proteins induced by MCP-1 treatment of human peripheral blood monocytes with MCP-1 and thus, named MCPIP. Since then it has been demonstrated that many inflammatory agents produced by M1 macrophages induce MCPIP. The promoter of the gene that encodes MCPIP contains multiple KLF4 binding sites. It was recently demonstrated that IL-4 treatment of murine macrophages induces not only STAT6 and KLF4 but also MCPIP as well Editorial