Targeting Beta Adrenergic Signaling for Autoimmune Pathologies

Interleukin 17A (IL-17A) is a potent pro-inflammatory cytokine involved in host immune defense and tissue repair, but also plays an important role in driving autoimmune pathologies such as multiple sclerosis, rheumatoid arthritis, and psoriasis. IL-17A neutralizing antibodies, such as secukinumab and ixekizumab, show promise in attenuating autoimmune pathology, but 1) only dampen IL-17A signaling as opposed to down-regulating its expression and 2) are extremely expensive and require continual injections. Therefore, additional anti-IL-17A adjuvant therapies are highly sought after for autoimmune pathology. Previously, we identified a novel role for both beta 1 and 2 (β1/2) adrenergic receptors in the production of IL-17A from T-lymphocytes. Specifically, we found that these receptors are expressed on T-lymphocytes, and together, directly regulate IL-17A production from these adaptive immune cells via catecholamine, cyclic AMP (cAMP), and protein kinase A (PKA) signaling pathways. Additionally, β1/2 blockade also led to phenotype switching to regulatory anti-inflammatory T-lymphocytes (Tregs). Moreover, both genetic and pharmacological blockade of β1/2 were able to significantly attenuate IL-17A expression (and increase Tregs) in a mouse model of post-traumatic stress disorder. Given these exciting results, we hypothesized that targeting β1/2 adrenergic signaling would also attenuate autoimmune pathology. To test this hypothesis, we employed both genetic and pharmacological blockade of β1/2 adrenergic signaling in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. First, we performed adoptive transfer of β1/2 knock-out T-lymphocytes into immunodeficient hosts, thus generating T-lymphocyte specific β1/2 knock-out animals. These animals demonstrated significantly attenuated IL-17A levels (p=0.0321), elevated IL-10 levels and Treg numbers (p=0.0330, p=0.0353), as well as lowered disease severity and delayed onset of EAE symptoms (p<0.0001) compared to animals receiving wild-type T-lymphocytes. These findings were replicated using pharmacological blockade of β1/2 signaling starting propranolol treatment 7 days after the initiation of EAE (p<0.0001), demonstrating its therapeutic efficacy. Interestingly, while wild-type animals treated with propranolol prior to EAE induction demonstrated significantly lowered IL-17A levels compared to controls (p=0.0154), their EAE symptomology was not attenuated to the level of the therapeutic delivery of propranolol. Taken together, our data suggest that β1/2 adrenergic blockade has promising potential as an adjuvant therapy for autoimmune diseases by limiting IL-17A production and enhancing anti-inflammatory Treg cells. R01HL158521 (AJC), F31HL176172 (THL) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.