Crosstalk between Microglia and Neurons in Neurotrauma: An Overview of the Underlying Mechanisms

Abstract

Microglia are the resident immune cells of the brain and play a crucial role in housekeeping and maintaining homeostasis of the brain microenvironment. Upon injury or disease, microglial cells become activated, at least partly, via signals initiated by injured neurons. Activated microglia, thereby, contribute to both neuroprotection and neuroinflammation. However, sustained microglial activation initiates a chronic neuroinflammatory response which can disturb neuronal health and disrupt communications between neurons and microglia. Thus, microglia-neuron crosstalk is critical in a healthy brain as well as during states of injury or disease. As most studies focus on how neurons and microglia act in isolation during neurotrauma, there is a need to understand the interplay between these cells in brain pathophysiology. This review highlights how neurons and microglia reciprocally communicate under physiological conditions and during brain injury and disease. Furthermore, the modes of microglia-neuron communication are exposed, focusing on cell-contact dependent signaling and communication by the secretion of soluble factors like cytokines and growth factors. In addition, it has been discussed that how microglia-neuron interactions could exert either beneficial neurotrophic effects or pathologic proinflammatory responses. We further explore how aberrations in microglia-neuron crosstalk may be involved in central nervous system (CNS) anomalies, namely traumatic brain injury (TBI), neurodegeneration, and ischemic stroke. A clear understanding of how the microglia-neuron crosstalk contributes to the pathogenesis of brain pathologies may offer novel therapeutic avenues of brain trauma treatment.

Keywords: CNS Injury; cellular crosstalk; microglia phenotypes; microglia-neuron interaction; microglial activation; neuroinflammation.

Fig. (1)

Microglial crosstalk in traumatic brain injury. Traumatic injury of the brain often results in a cascade of detrimental outcomes that involve a variety of resident and peripheral cells. At the site of injury, damaged neurons release substantial amounts of ATP, cellular debris, extracellular vesicles, and an assortment of mediators collectively responsible for the activation of microglial cells. This activation is also the result of disrupted microglia-neuron communication signals (e.g., CX3CL1-CX3CR1 signaling) between injured neurons and microglia. Damaged neurons stimulate the activation of microglia, which, once activated, secrete molecules, such as IL-1α, C1q, and TNF-α, and activate astrocytes. Reactive astrocytes, in turn, exert their effect on microglia, neurons, oligodendrocytes, and the BBB. The BBB is then rendered more permeable to such cells as monocytes, macrophages, and T-cells, which infiltrate the CNS and exacerbate the inflammatory response initially produced by microglia, thereby causing further damage and toxicity to the BBB and the brain. Depending on the extent and severity of the trauma, the complex crosstalk between the cells of the CNS may either be destructive, leading to excitotoxicity, neuroinflammation, demyelination, apoptosis, and other complications, or neuroprotective, promoting repair and survival.