Fig. 5

Synergistic immuno-modulatory effects of cyclic AMP and IL-4 in the M1 to M2a phenotypic conversion of microglia. Subjecting resting (M0) microglia to a pro-inflammatory stimulus, TNF-α or LPS, drives the cells to a classically activated (M1) phenotype. The M1 form displays high expression of cytokines and chemokines, such as TNF-α and IP-10, as well as iNOS and free radicles, ROS and RNS, that are key in cytotoxicity and tissue injury. In addition, the production of tissue reparative and remodeling enzymes, such as ARG-1, YM1, RELM-α, and TG, are suppressed. In contrast, the concurrent exposure of M0 or M1 microglia to IL-4 and cyclic AMP induces M0/M1 phenotype conversion to a robust reparative M2a form. The M2a phenotype exhibits strong expression of ARG-1, TG2, RELM-α, and YM1, an augmented phagocytic ability and the absence of pro-inflammatory cytokine and toxic reactive radical production that are associated with the M1 form. When M0- or M1-activated microglia are exposed to IL-4 alone, there is a transition to an intermediate M2a form. The M2a phenotype retains partial characteristics of M1 while acquiring some beneficial characteristics of the M2 phenotype, though exhibits impaired phagocytic function