Mechanisms of microglial activation in models of inflammation and hypoxia: Implications for chronic intermittent hypoxia

Abstract

Chronic intermittent hypoxia (CIH) is a hallmark of sleep apnoea, a condition associated with diverse clinical disorders. CIH and sleep apnoea are characterized by increased reactive oxygen species formation, peripheral and CNS inflammation, neuronal death and neurocognitive deficits. Few studies have examined the role of microglia, the resident CNS immune cells, in models of CIH. Thus, little is known concerning their direct contributions to neuropathology or the cellular mechanisms regulating their activities during or following pathological CIH. In this review, we identify gaps in knowledge regarding CIH-induced microglial activation, and propose mechanisms based on data from related models of hypoxia and/or hypoxia-reoxygenation. CIH may directly affect microglia, or may have indirect effects via the periphery or other CNS cells. Peripheral inflammation may indirectly activate microglia via entry of pro-inflammatory molecules into the CNS, and/or activation of vagal afferents that trigger CNS inflammation. CIH-induced release of damage-associated molecular patterns from injured CNS cells may also activate microglia via interactions with pattern recognition receptors expressed on microglia. For example, Toll-like receptors activate mitogen-activated protein kinase/transcription factor pathways required for microglial inflammatory gene expression. Although epigenetic effects from CIH have not yet been studied in microglia, potential epigenetic mechanisms in microglial regulation are discussed, including microRNAs, histone modifications and DNA methylation. Epigenetic effects can occur during CIH, or long after it has ended. A better understanding of CIH effects on microglial activities may be important to reverse CIH-induced neuropathology in patients with sleep disordered breathing.

Figure 1. Model of CIH‐induced inflammation via microglial TLR4 activation

Damage‐associated molecular patterns (DAMPs) are endogenous TLR4 ligands that are among the factors released from stressed and dying cells. Chronic intermittent hypoxia increases several DAMPs that can bind TLR4 in microglia and activate canonical inflammatory signalling cascades. TLR4 signalling utilizes two different pathways: MyD88‐dependent and TRIF‐dependent. The MyD88‐dependent pathway increases pro‐inflammatory gene expression through activation of the MAP kinases ERK, p38 and JNK, and transcription factors including NF‐κB and AP‐1. The TRIF‐dependent pathway induces phosphorylation of IRF3, which then translocates to the nucleus and induces expression of type I interferons (IFNs) such as IFNβ and anti‐inflammatory cytokines. Both MyD88 and TRIF proteins are increased peripherally and centrally after CIH.