Immune cells and CNS physiology: Microglia and beyond

Abstract

Recent advances have directed our knowledge of the immune system from a narrative of "self" versus "nonself" to one in which immune function is critical for homeostasis of organs throughout the body. This is also the case with respect to the central nervous system (CNS). CNS immunity exists in a segregated state, with a marked partition occurring between the brain parenchyma and meningeal spaces. While the brain parenchyma is patrolled by perivascular macrophages and microglia, the meningeal spaces are supplied with a diverse immune repertoire. In this review, we posit that such partition allows for neuro-immune crosstalk to be properly tuned. Convention may imply that meningeal immunity is an ominous threat to brain function; however, recent studies have shown that its presence may instead be a steady hand directing the CNS to optimal performance.

Figure 1.

Homeostatic functions of microglia. (A) At various time points of neurogenesis, microglia display a critical role in regulating the number of neural progenitors through phagocytosis (Marín-Teva et al., 2004; Squarzoni et al., 2014; Ribeiro Xavier et al., 2015). (B) Microglia respond acutely to CNS damage by sensing ATP through P2RY12 signaling (Davalos et al., 2005). (C) Engulfment of synaptic material in development and disease is regulated by complement-mediated recognition (Hughes, 2012; Kettenmann et al., 2013). (D) Homeostatic surveillance by microglial processes is regulated by the potassium channel THIK-1 (Madry et al., 2018).

Figure 2.

Meningeal immune-derived cytokines regulate CNS function. Recent publications have documented roles for the CD4 T cell–derived cytokines IL-4 (Derecki et al., 2010), IFN-γ (Filiano et al., 2016), and IL-17 (Choi et al., 2016) in brain function. T cell–derived ACh has been shown to play a profound role in suppressing autoimmune processes (Chavan et al., 2017) and regulation of blood pressure (Olofsson et al., 2016) while its role in meningeal immunity has not been investigated. ILC2-derived IL-5 and IL-13 is critical for host defense of pathogens in both gut and lung (Cardoso et al., 2017; Klose et al., 2017). While ILC2s are prevalent in the meninges (Gadani et al., 2017), the role of ILC2-derived cytokines in CNS function is unknown.