Abstract 031: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation by Altering Autonomic Output
Endoplasmic reticulum (ER) stress is a contributing factor in a variety of chronic diseases. We previously showed that ER stress in the SFO is involved in the activation of the adaptive immune system, which is causally linked with hypertension. However, the exact mechanism by which ER stress in the SFO activates peripheral T cells remains unclear. Recently it has been shown that the SFO is involved in modulating autonomic output to stimulate T cells. Here we tested if ER stress in the SFO increases autonomic drive to stimulate peripheral T cell proliferation. Five days of intracerebroventricular (ICV) delivery of the ER stress inducer thapsigargin (Tg, 1 μg/day) resulted in significant increases in peripheral T cells in aorta and blood as measured by flow cytometry (Aorta: Veh, 2.1 ± 0.7 vs. Tg, 10.1 ± 2.8 x 103 cells/aorta; Blood: Veh, 17.8 ± 1.3 vs. Tg, 34.8 ± 4.7 % of CD45+ cells, n=8-13, p<0.05). ER stress in the brain resulted in a marked increase in plasma norepinephrine (Veh: 285 ± 28 vs. Tg: 406 ± 45 pg/mL, n=4-5, p<0.05). We also found that the effect of ICV Tg to increase peripheral T cells was blocked by hexamethonium (Hex, i.p., 30 μg/g) (Aorta: Tg, 10.1 ± 2.8 vs. Tg+Hex, 3.1 ± 0.4 x 103 cells/aorta; Blood: Tg, 34.8 ± 4.7 vs. Tg+Hex: 21.4 ± 1.9 % of CD45+ cells, n=6, p<0.05). Consistent with earlier findings, ICV infusion of Tg increased ER stress markers in the SFO (CHOP: Veh, 1.15 ± 0.106 vs. Tg, 3.285 ±1.04; grp78: Veh, 1.032 ± 0.13 vs. Tg, 3.065 ± 1.102; p58IPK: Veh, 0.85 ± 0.213 vs. Tg, 7.065 ± 2.588, fold change, normalized to 18S, n=4-6, p<0.05), but did not alter the expression of these markers in aortas. This suggests that T cell activation is centrally mediated and not caused by peripheral vascular ER stress or inflammation. In conclusion, our data suggest that ER stress in the SFO modulates autonomic nervous system output and activates the peripheral immune system, a hallmark of the development of hypertension.
Author Disclosures: H.E. Lob: None. J. Song: None. A. Chung: None. S.D. Butler: None. A.L. Mark: None. R.L. Davisson: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.