Functional plasticity of macrophages: reversible adaptation to changing microenvironments

Abstract: There has been substantial research ac-tivity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The em-phasis over the past 2–3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition recep-tors, hormones) differentially regulates macro-phage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a pro-gression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macro-phages to adapt to changes in their microenviron-ment challenges the thesis that macrophages dis-playing unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and ma-ture dendritic cells, evidence supporting stable dif-ferentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as op-posed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macro-phages in disease pathogenesis. J. Leukoc. Biol