Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats

Abstract

Our previous studies showed more severe EAE in male compared with female adult rats, and moderating effect of propranolol‐induced β‐adrenoceptor blockade on EAE in female rats through stimulation of Nrf2/HO‐1 signalling pathway in spinal cord microglia. This study was designed to examine putative sexual dimorphism in Nrf2/HO‐1 signalling pathway and CX3CL1, as one of its activators. Propranolol treatment beginning from the appearance of the first clinical signs of EAE mitigated the disease severity in rats of both sexes, but its effect was more prominent in males. This correlated with more prominent effect of propranolol on the expression of CX3CL1 in spinal cord tissue, CX3CR1 on microglial surface, and Nrf2/HO‐1 in spinal cord microglia in males. Consistently, the proportion of CX3CR1‐expressing microglia and CX3CR1 density on their surface increased more prominently in males. Consistently, propranolol increased the proportion of IL‐10/TGF‐β‐producing microglia and microglia expressing CD163, molecule highlighting ramified microglia with neuroprotective properties in damaged tissue, to a greater extent in males. Additionally, propranolol increased phagocyting capacity of microglia to a greater extent in males. Moreover, propranolol more prominently decreased the frequency of blood‐borne myeloid cells and highly pathogenic IL‐17+ T‐cells, coexpressing GM‐CSF/IFN‐γ, in male rat spinal cord. This correlated with greater reducing effect of propranolol on the spinal cord tissue expression of CCL2/CCL19/CCL21 chemokines in males. The study as a whole indicates that sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis could contribute to greater severity of EAE in male rats, and sexually dimorphic action of substances affecting its signalling capacity.