Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity.
Excitotoxicity underlies neuronal death in many neuropathological disorders, such as Alzheimer's disease and multiple sclerosis. In murine models of these diseases, disruption of CX3CR1 signaling has thus far generated data either in favor or against a neuroprotective role of this crucial regulator of microglia and monocyte functions. In this study, we investigated the recruitment of circulating PU.1-expressing cells following sterile excitotoxicity and delineated the CX3CR1-dependent neuroprotective functions of circulating monocytes versus that of microglia in this context. WT, Cx3cr1-deficient and chimeric mice were subjected to a sterile excitotoxic insult via an intrastriatal injection of kainic acid (KA), a conformational analog of glutamate. Following KA administration, circulating monocytes physiologically engrafted the brain and selectively accumulated in the vicinity of excitotoxic lesions where they gave rise to activated macrophages depicting strong Iba1 and CD68 immunoreactivity 7 days post-injury. Monocyte-derived macrophages completely vanished upon recovery and did thus not permanently seed the brain. Furthermore, Cx3cr1 deletion significantly exacerbated neuronal death, behavioral deficits and activation of microglia cells following sterile excitotoxicity. Cx3cr1 disruption also markedly altered the blood levels of patrolling monocytes 24 h after KA administration. The specific elimination of patrolling monocytes using Nr4a1(-/-) chimeric mice conditioned with chemotherapy provided direct evidence that these circulating monocytes are essential for neuroprotection. Taken together, these data support a beneficial role of CX3CR1 signaling during excitotoxicity and highlight a novel and pivotal role of patrolling monocytes in neuroprotection. These findings open new research and therapeutic avenues for neuropathological disorders implicating excitotoxicity.
Neuroscience Laboratory, Department of Molecular Medicine, Faculty of Medicine, CHU de Québec Research Center, Laval University, 2705 Laurier Blvd., Quebec, G1V 4G2, Canada, marc-a.bellavance@crchul.ulaval.ca.
Marc-André
MA
Bellavance
David
D
Gosselin
V Wee
VW
Yong
Peter K
PK
Stys
Serge
S
Rivest
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology* / Q000187:drug effects; D008845:Microinjections / Q000379:methods; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; D007608:Kainic Acid; D008840:Microfilament Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019707:Receptors, Chemokine; C491049:Aif1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C471885:Cx3cr1 protein, mouse; C539818:Nr4a1 protein, mouse