β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males

Abstract

Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimorphism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte trafficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.

Chronic Effects of the Sympathetic Nervous System in Inflammatory Models

“…On the other hand, systemic sympathetic modulation via βARs also shows a biphasic effect in EAE, however, with an anti-inflammatory effect in peri-induction/early phase and a proinflammatory effect when intervention starts after induction of EAE [29, 30]. This result is just contrary to observations from colitis and arthritis.…”

“…As an additional finding, the latter and further studies noted a difference in the response of the SNS between female and male subjects, leading to the assumption that the male SNS is more reactive in an inflammatory context leading to overall pronounced neuromodulatory effects in males [29, 76, 77]. A sexual dimorphism of the structure of the locus coeruleus as well as the bed nucleus of the stria terminalis has been described [78, 79], which could be associated with these differences and might have further implications maybe contributing to sex-differences in incidence and severity of autoimmune diseases in general.…”

“…Besides regulation of inflammation, many studies also investigated changes in local neurotransmitters, like noradrenaline (NA), by inflammation, e.g., in the EAE model [31, 80, 81]. One study suggests a biphasic pattern for catecholamine content with no change or increase in neurotransmitters in the early phase and a decrease in the later phase of EAE, again with more pronounced changes in male as compared to female rats [29]. On the contrary, peripheral intracellular NA levels are increased in PBMCs of MS patients and decreased under treatment with INF-β [82, 83].…”