A Novel Beta-Adrenergic Signaling Mechanism Drives Interleukin 17A (IL-17A) and Hypertension by Chronic Stress

About This Grant

PROJECT SUMMARY Recurrent and chronic stress is an independent risk factor for the development of cardiovascular disease, including hypertension, but the mechanisms linking psychopathology to cardiovascular pathology remain undefined. Dysregulation of the immune system and inflammation have been hypothesized as intermediates between the brain and cardiovascular system during stress. Indeed, in a model of chronic stress known as repeated social defeat stress (RSDS), we have previously identified that RSDS exacerbates the blood pressure rise induced by angiotensin II (AngII) in an inflammation-dependent manner. Specifically, we have found that the overproduction of interleukin 17A (IL-17A) by T-lymphocytes is causal to the RSDS-induced blood pressure sensitization to AngII. Therefore, deciphering how chronic stress leads to increased IL-17A production from T-lymphocytes provides an opportunity for therapeutic intervention. Importantly, it has been widely accepted that IL-17A production from T-lymphocytes requires the presence of both transforming growth factor beta (TGFβ) and interleukin 6 (IL-6). However, we have recently discovered that T-lymphocytes are still able to produce IL-17A in the absence of IL-6 during RSDS, which suggests a novel signal replaces IL-6 during stress. Our research strongly indicates that this replacement signal is norepinephrine (NE) signaling through beta (β)-adrenergic receptors expressed on T-lymphocytes, which puts forth an unexplored pathway of IL-17A production. Our preliminary data implicate that TGFβ in combination with NE activates STAT3 to lead to IL-17A transcription, similar to TGFβ and IL-6, but does so utilizing a currently undefined pathway utilizing cyclic AMP (cAMP), protein kinase A (PKA), and ERK1/2, which differs from canonical TGFβ and IL-6 signaling. Together, this proposal will investigate the overarching hypothesis that NE signaling replaces IL-6 in T-lymphocyte IL-17A production via unique β-adrenergic signaling pathways that coalesce on STAT3 activation. Additionally, this novel pathway appears essential to stress-induced IL-17A release, which causes an exacerbated AngII hypertensive response. Our two Specific Aims are designed to determine the mechanistic roles and signaling of T-lymphocyte β-adrenergic receptors and cAMP/PKA/ERK1/2 in stress-induced IL-17A production and the exacerbated AngII blood pressure response. Our discovery that NE signaling through β-adrenergic receptors effectively replaces IL-6 as a necessary component to T-lymphocyte IL-17A production provides a new and exciting paradigm shift in our understanding of IL-17A regulation, and has major clinical implications for limiting cardiovascular disease and dysregulated blood pressure control stemming from recurrent and chronic stress.