Central fractalkine–CX3CR1 signaling mediates systemic LPS-induced inhibition of LH pulses in female rats

Inflammatory diseases often suppress reproductive function in mammals. This study investigated whether central fractalkine-CX3CR1 signaling mediates the inhibition of luteinizing hormone (LH) release induced by intravenous administration of lipopolysaccharide (LPS), an endotoxin, in ovariectomized (OVX) rats treated with diestrous levels of estradiol-17β (E2). Double in situ hybridization (ISH) for the fractalkine gene (Cx3cl1) and fos (a cellular activation marker) revealed that LPS significantly increased the percentage of fos-positive Cx3cl1-expressing cells in the lateral mammillary nucleus (LM) and the number of Cx3cl1-expressing cells in the paraventricular nucleus (PVN). Central administration of AZD8797, an CX3CR1 antagonist significantly restored LPS-induced decreases in the mean LH concentrations and the amplitude and baseline of LH pulses. Furthermore, LPS administration significantly increased the percentage of fos-positive fractalkine receptor gene (Cx3cr1)-expressing cells in the arcuate nucleus (ARC), whereas AZD8797 treatment significantly attenuated this LPS-induced increase. ISH for Cx3cr1 and Iba1 (a microglial marker) immunohistochemistry revealed that most Cx3cr1-expressing cells were Iba1-positive. Additionally, Cx3cr1-positive signals were observed adjacent to kisspeptin gene (Kiss1)-expressing cells in the ARC, although a few ARC Kiss1-expressing cells also exhibited Cx3cr1 expression. Collectively, these findings demonstrate that central fractalkine-CX3CR1 signaling, at least in part, mediates the suppression of LH pulses induced by systemic LPS. LM and PVN fractalkine neurons might suppress ARC kisspeptin neurons-the center for gonadotropin-releasing hormone/LH pulse generation-via neighboring CX3CR1-expressing microglial cells. These findings may contribute to the development of therapeutic strategies to mitigate inflammation-associated reproductive dysfunction in both livestock and humans.