Reversible differentiation of pro- and anti-inflammatory macrophages

Macrophages (Mφ) represent dynamic cell populations that develop according to the nature of environmental signals. It has been demonstrated that human Mφ can be polarized in vitro into pro-inflammatory (Mφ1) and anti-inflammatory cells (Mφ2) by the lineage-determining factors GM-CSF and M-CSF, respectively. Here we show that polarized Mφ1 and Mφ2 are not an end stage of differentiation but are able to reversibly undergo functional re-differentiation into anti-inflammatory and pro-inflammatory Mφ. GM-CSF-driven Mφ1 exposed to M-CSF for an additional 6 days obtained a Mφ2-like phenotype, inhibited the production of pro-inflammatory cytokine IL-6 and TNF-α, and exhibited a reduced T cell stimulatory capacity. Vice versa, Mφ2 exposed to GM-CSF exhibited a Mφ1-like phenotype with significant lower production of anti-inflammatory cytokine IL-10 and a higher T cell stimulatory activity, and a decreased capacity for phagocytosis of early apoptotic cells. Our data suggest that polarized macrophages are flexible in modulating their immune functions upon environmental changes, i.e., steady-state versus inflammatory conditions. These observations are important for our understanding of the regulatory role of macrophages in tissue homeostasis and disease pathogenesis.