Myeloid Cells in the Central Nervous System

Abstract

The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions.

Keywords: autoimmune; dendritic cells; granulocytes; infection; injury; macrophages; meninges; microglia; monocytes; neurodegeneration.

Figure 1. CNS-associated myeloid cells in homeostasis

Within the complex anatomy of the brain and spinal cord, myeloid cells are strategically positioned in the parenchyma, nearby its blood vessels and within the meninges, where they fulfill homeostatic and surveillance tasks. While microglia are situated in the parenchyma and actively scan intraneuronal space, macrophages, dendritic cells and mast cells reside in the linings such as the meninges and choroid plexus and sample local debris and intruders from the blood and cerebrospinal fluid (Goldmann et al., 2016a). The communication with the peripheral immune system is presumably happening through meningeal lymphatic vessels, through which meningeal immune cells and soluble molecules drain to the deep cervical lymph nodes. It is important to note that depletion of myeloid cells in the CNS compartments leads to disturbed neurogenesis, impaired blood-brain barrier integrity and neuronal dysfunction.

Figure 2. CNS modulating roles of microglia

Microglia contribute to neuronal health but also participate in neuronal dysfunction and morphologic abnormalities. Left: The neuro-supportive role of microglia is mediated by secretion of trophic factors, such as BDNF (brain-derived neurotrophic factor) (Parkhurst et al., 2013) and participation of pruning as part of the normal developmental program (Paolicelli et al., 2011; Stevens et al., 2007). Their phagocytic activity is crucial for the cleanup of senescent cells and debris (Takahashi et al., 2005) and slowing the toxic effect of amyloid-β (Farfara et al., 2011). Right: Without vital microglia function, the CNS loses an essential facilitator of neuronal synaptic function (Parkhurst et al., 2013). Interactions with neurons promote plasticity but aberrant activity may facilitate intense inflammatory reactions that result in CNS pathology (Zhang et al., 2011). Phagocytic pursuit declines with age and can promote the progression of pathology and lead to cognitive regression (Hickman et al., 2008).

Figure 3. Monocytes roles in CNS diseases

In EAE, monocytes apply cytotoxic effects on neurons and trigger disease progression by stripping myelin. Contrary, after traumatic injury peripherally derived monocytes are required to remove cellular debris and ultimately promote regeneration. In Alzheimer’s disease, monocytes potentially reduce amyloid loads in the brain through enhanced clearance of amyloid plaques. However, most recent data argue against the possibility that monocytes infiltrate the CNS so their involvement is questionable. Targeting circulating Ly6C+ monocytes slowed amyotrophic lateral sclerosis (ALS) progression and attenuated neuronal damage. Their presence and potentially damaging actions within the CNS remain controversial.