Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity

Abstract

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.

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

“…Immunologic depletion of neutrophils and monocytes reduced neuronal injury caused by kainate in mice, and the infiltrating neutrophils appeared to be phagocytosed by resident microglia or monocyte-derived macrophages [60]. These observations are consistent with the well-recognized exacerbation of tissue injury by neutrophils in peripheral tissues [90]. …”

“…Granulocytes (presumably mostly neutrophils) begin to infiltrate cortex and hippocampus a few hours after SE onset in rats and mice, and are commonly observed in different SE models [59,60,90]. Immunologic depletion of neutrophils and monocytes reduced neuronal injury caused by kainate in mice, and the infiltrating neutrophils appeared to be phagocytosed by resident microglia or monocyte-derived macrophages [60].…”

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

“…However, ablation of brain-resident myeloid precursors via busulfan treatment caused the long-term turnover of CNS microglia by the engrafted bone marrow-derived cells [114]. Following kainic acid administration with BU and cyclophosphamide treatment, circulating monocytes physiologically engrafted the brain and gave rise to activated macrophages [115]. These studies indicated the feasibility of chemotherapies to induce the generation of BM-derived microglia.…”

Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders

“…It is also likely that the rate of BU administration modifies its toxicity such as fractionating the dose through multiple injections over few days would provoke considerably less toxicity than the equivalent dose administered acutely. As a matter of fact, the chemotherapeutic conditioning consisting of 80 mg/kg of BU and 200 mg/kg of cyclophosphamide is routinely used in our lab [107][108][109] and never led to artificial engraftment of BMDC under non-pathological conditions. There is a serious need for other experiments to determine how the dose of BU influences BMDC recruitment to the brain.…”

“…While the precise mechanism has still not been defined, beneficial effects of patrolling monocytes were reported following kainic acid (KA)-induced excitotoxicity [107]. On the other hand, CCR2 − Ly6C low patrolling monocytes ablation by WBI and BMT of Nr4a1 −/− cells in a model of stroke had no effect on the functional outcomes, lesion size, cell death, or number/activation of mononuclear phagocytes at the lesion [184].…”