Heterogeneity of microglial activation in the innate immune response in the brain

Abstract

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain's innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed.

Fig. 1

Arginase–NOS2 balance. Arginine is taken up by arginine transporters where it is used by both arginase 1 and nitric oxide synthase. Arginase pathways produce polyamines and ECM while NOS pathways produce N-hydroxy arginine (an inhibitor of arginase (N-OH-arg)), nitric oxide (NO), and citrulline

Fig. 2

Acquired deactivation