TABLE 2.

Various roles of CCR5 in the CNS during healthy and diseased states.

Condition	Cell type	Role of CCR5 in CNS	References
Normal	Neural progenitor cells	Induces neural progenitor cells to migrate and promotes neuronal differentiation	Ji et al., 2004; Park et al., 2009
	Neuron	Promotes neuronal growth and differentiation during embryonic development	Bolin et al., 1998; Park et al., 2009
		Modulates neuronal excitability and neurotransmitter release	Oh et al., 2002; Musante et al., 2008
		Regulates neuronal survival or apoptosis	Choi et al., 2013; Radzik et al., 2019
		Inhibits hippocampus and cortical plasticity, impairs learning and memory processes	Zhou et al., 2016; Necula et al., 2021
	Microglia	Mediates microglia migration and colonization, which may provide nutritional support, regulation of neuronal development, and removal of toxic debris	Polazzi and Contestabile, 2002; Cowell et al., 2006
	Astrocytes	Regulates the proliferation, survival and differentiation of astrocyte progenitors during embryonic development	Bakhiet et al., 2001; Cartier et al., 2005; Necula et al., 2021
Ischemic stroke	Neuron	Inhibits neuronal plasticity and recovery	Joy et al., 2019; Joy and Carmichael, 2021
	Astrocytes	Promotes astrocytes proliferation and activation	Liraz-Zaltsman et al., 2021
	Monocytes	Recruites monocytes and modulates the immune response	Cartier et al., 2005
	Treg cells	Mediates the docking of transferred Tregs to relieve neutrophil accumulation and protect BBB	Sorce et al., 2010; Li et al., 2017
	Neutrophils	Induces neutrophils migration toward the injured area and leads to deteriorated brain injury	Chen et al., 2020
Intracerebral hemorrhage	Neuron	Mediates neurological deficits and neuronal pyroptosis via CCR5/PKA/CREB pathway	Yan et al., 2021
Neuroinflammation	Microglia	Induces microglia proliferation and activation	Louboutin and Strayer, 2013
	Monocytes	Mediates monocyte migration and affects the leakage of BBB	Ubogu et al., 2006; Louboutin et al., 2011
Infectious disease
West Nile virus infection	Monocytes, Macrophages, NK cells, and T lymphocytes	Regulates trafficking of leukocytes to CNS to contain and clear the virus	Glass et al., 2005
Mouse Hepatitis Virus intracranial infection	Macrophages	Mediates macrophage trafficking into CNS and leads to demyelination	Glass et al., 2001
HIV-Associated Neurocognitive Disease (HAND)	CD4+ T lymphocytes	Mediates HIV-1 entry into CD4+ cells as a fusion cofactor	Kwong et al., 1998
	Microglia	Promotes microglial activation and neuronal damage, thereby improved cognition	Maung et al., 2014; D’Antoni et al., 2018
	Monocytes	Recruits HIV-infected monocytes to CNS and leads to intracranial infection and inflammation.	Hahn et al., 2010
Cerebral malaria	CD8+ T lymphocytes	Regulates trafficking of CD8+ T lymphocytes to destroy brain endothelial cells and BBB	Belnoue et al., 2003
Cancer
Primary central nervous system lymphomas	Malignant B lymphocytes	Induces B lymphocytes homing to the brain and spreading within CNS	Brunn et al., 2007
Glioblastoma	Glioma-associated microglia/macrophages (GAMs)	Induces glioma invasive process	Yu-Ju Wu et al., 2020
		Regulates M1/M2 microglia phenotype	Laudati et al., 2017
	Treg cells, Monocyte	Recruits immunosuppressive cells to induce immune tolerance	Jiao et al., 2019
	Tumor cell	Promotes tumor cell proliferation and migration	Aldinucci and Colombatti, 2014
Pathological pain	Neuron	Activates neuron ERK to create and maintain pathological pain	Piotrowska et al., 2016; Hang et al., 2017; Lu et al., 2017
		Reduces the antinociceptive action of opioid receptor agonists	Szabo et al., 2002; Chen et al., 2007
Multiple sclerosis (MS)	T lymphocytes	Regulates trafficking of inflammatory T cells into CNS to induce self-destructive inflammatory process	Zang et al., 2000; Menten et al., 2002; Schlager et al., 2016
Neurodegenerative disease
Alzheimer’s disease (AD)	Microglia, Astrocytes	Recruits and activates astrocytes and microglia to affect amyloid deposition and memory function with CCR2	Cartier et al., 2005; Lee et al., 2009; Goldeck et al., 2013
Parkinson’s disease (PD)	neuron	Promotes maturation of nigral dopaminergic neurons	Choi et al., 2013