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Figure 1. Schematic representation of microglial process contacts in health and disease. Illustration demonstrating various microglial and monocytic contacts onto axonal segments. A: in the healthy brain, resident microglia (green) contact the neuronal cell body and axon initial segment. These microglia potentially express TNF-α and CSF1 and are involved in reduction of hyperexcitability in neurons. The dynamic surveying processes of non-activated ramified microglia also contact various areas of the axon in the healthy CNS. During development, contacts by resident microglia are involved in pre- and postsynaptic pruning; B: in MS, both resident microglia (green) and infiltrating peripheral monocytes (red) contact the nodes of Ranvier. Note that the processes of monocytes are found between the layers of myelin and the axon sheath, while the resident microglial processes are primarily in contact with adjacent monocytes and/or involved in debris clearance. Neuroinflammatory cells that have yet to be identified as either resident microglia or infiltrating monocytes (teal) that express TNF-α, INOS, Nox2, and higher levels of activated calpain, wrap the axon initial segment. This wrapping is involved in a notable reduction in the length of the axon initial segment; C: following TBI, macrophages (monocytes and/or microglia) phagocytosis the Wallerian debris from the degenerating distal axonal segments of an injured axons. Potential hyperexcitability of neurons following TBI induces microglial process convergence onto the neuronal soma via elevated ATP levels and/or glutamate levels. Rod microglia (green) are also common along the apical dendrite following injury; however, their function is currently unknown. Microglial process convergence onto the proximal injured axonal segment is associated with P2Y12 and potentially confers neuroprotective effects on the damaged axon leading to axonal sprouting. CNS: central nervous system; MS: multiple sclerosis; TBI: traumatic brain injury; TNF: tumor necrosis factor; CSF1: colony stimulating factor 1; INOS: inducible nitric oxide synthase; Nox2: NADPH oxidase 2