Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS) characterized by an autoimmune response where both T-lymphocytes and proinflammatory interleukin 17A (IL-17A) are implicated in the pathogenesis of the disease. We recently identified a molecular mechanism involving beta-adrenergic 1 and 2 receptors (β1/2) in the polarization of TH17 lymphocytes. Pharmacological and genetic inhibition of these receptors in combination, but not separately, impaired the ability of T-lymphocytes to produce IL-17A and instead promoted the differentiation of protective Treg cells that secrete anti-inflammatory interleukin-10 (IL-10). However, it remained unclear whether this regulatory mechanism could serve as a novel therapeutic approach for autoimmune disorders mediated by IL-17A-producing T-lymphocytes, like MS. Using an animal model of MS, termed experimental autoimmune encephalomyelitis (EAE), we addressed the impact of beta adrenergic receptor blockade (genetically and pharmacologically) on EAE disease progression, severity, and TH17/Treg balance. Genetic deletion β1/2 receptors, either systemically or specifically on T-lymphocytes, significantly attenuated EAE disease severity and animal weight loss. Therapeutic pharmacological blockade of β1/2 receptors with either propranolol (lipophilic) or nadolol (aqueous) limited disease severity and weight loss similar to the genetic models, with combination therapy with anti-IL-17A antibodies showing the greatest disease remission. All models showed degrees of shifted TH17/Treg balance and decreased T-lymphocyte IL-17A production. Our data depict a novel role for β1/2 adrenergic signaling in the control of TH17/Treg cells in EAE, and provide new insight into the disease progression as well as offer a potential new pharmacological therapy for IL-17A-related autoimmune diseases.