Identification of a Novel Tlymphocyte Inflammatory Protein in Psychological Stress Induced Hypertension
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Posttraumatic stress disorder (PTSD) is a psychiatric condition characterized by hyperarousal, anxiety, anhedonia, and depression. While the behavioral manifestations are often the focus of this disease, PTSD also alters physiological processes leading to elevated sympathetic tone and norepinephrine (NE) outflow, pronounced inflammation, and a >50% increased risk in developing comorbid cardiovascular diseases like hypertension. Our laboratory previously reported that exposure to NE can modulate levels of Tlymphocyte proinflammatory cytokines, and understanding that hypertension is regulated in part due to inflammation, we posited a connection between the autonomic nervous, immune, and cardiovascular systems in PTSD patients. We hypothesized that psychological stressinduced sympathoexcitation leads to increased proinflammatory cytokine production from Tlymphocytes, which impacts the development of hypertension. Utilizing a mousemodel of PTSDlike psychological trauma, lymphatic sympathoexcitation was confirmed by a 2.5 fold increase in NE and 4.1 fold increase in tyrosine hydroxylase content in spleens from stressed animals (p<0.001). This increased sympathetic tone correlated with elevated proinflammatory cytokines IL17A, IL6, and IL2 (+4.4, +3.1, and +3.0 fold, respectively, p<0.01) both in circulation and also specifically within splenic Tlymphocytes. Examination of hemodynamics in the stressed mice elucidated a stable increase in resting mean arterial pressure (+19.5 mmHg, p<0.05) over the stressinduction period with an even greater (+39.8 mmHg, p<0.01) rise after stress context reexposure compared to control animals. To investigate the causal contribution of Tlymphocytes in driving this hypertensive response, recombination activating gene 2 (Rag2) knockout animals, devoid of mature lymphocytes, were utilized. Rag2 knockout mice showed no changes in proinflammatory cytokines, a 75% decrease in splenic TH levels (p<0.01), and a blunted blood pressure response upon context reexposure (+8.8 mmHg, p<0.01). Single cell RNAseq analysis of Tlymphocytes from stressed wildtype animals demonstrated a significant increase (p=8.61019) in calprotectin (S100a8 and S100a9) mRNA levels compared to control. Calprotectin is both an intracellular and extracellular protein involved in many inflammatory processes, but has been thought to be granulocytespecific making its detection in Tlymphocytes highly unexpected. We confirmed 40 and 30fold increases in S100a8 and S100a9 mRNA, respectively, in purified Tlymphocytes from stressed animals by qRTPCR (p<0.01). Additionally, a 3fold increase (p<0.001) in levels of calprotectin protein was observed in circulation of stressed animals. Last, we identified an approximate 2fold increase (p<0.05) in calprotectin protein levels in circulation from human patients with PTSD with comorbid hypertension compared to PTSD alone. Taken together, our data suggest a new role for Tlymphocytes in the regulation of stressinduced inflammation and hypertension, and present an undescribed protein target for future investigation and potential therapeutic intervention.Support or Funding InformationNIH R00HL123471This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
