Fractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis

Abstract

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal–microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal–microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a “find-me” signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a “find me” signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

“…High CCL20 levels contribute to the formation of bone metastases in breast cancer [44]. CX3CL1 (also known as fractalkine or neurotactin) is a membrane-bound chemokine that can facilitate intercellular interactions, interacts with the TNFα-converting enzyme ADAM17 and is released in its shed form by apoptotic cells to recruit professional phagocytes to the site of cell death [45,46]. Fractalkine serum concentrations were higher in patients with the ER/ PR negative tumours, which is in line with the literature.…”

Plasma Chemokines in Patients with Alcohol Use Disorders: Association of CCL11 (Eotaxin-1) with Psychiatric Comorbidity

“…Moreover, rats treated with acute ethanol displayed a decrease in CXCL12 levels after 4 h, which is congruent with the data from repeated experiments. Regarding plasma CX 3 CL1, most studies on the effects of alcohol are focused on the CNS (30, 31) and pancreas (32, 33) but a recent study has reported elevated concentrations of CX 3 CL1 in the serum of mice treated chronically (5 months) with ethanol (26), which is in opposition to our data in AUD patients but compatible with our preclinical data since ethanol-treated rats had higher plasma CX 3 CL1 concentrations, especially in rats acutely treated. However, it is important to indicate that species, doses and intensity of the exposure were not comparable in between these studies and that further research is needed to understand the time-course of the changes in chemokines in plasma after acute and chronic alcohol exposure.…”

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

“…The possibility that the activation of microglia in the diabetic brain may contribute to inflammatory injury has not been fully investigated, although the microglia activation pathway in the hypothalamus has been documented in diabetes [85]. Stress signals that induce inflammasome formation include chemokines and damage-associated molecular patterns, such as the high mobility group proteins HMGB1 and ATP [86–88]. For the therapeutic targeting of inflammasome formation induced by mitochondrial injury, sirtuins appear to show promise [89, 90].…”