Induction of Mucosal Tolerance to Collagen Type V Attenuates Hypoxic Pulmonary Hypertension

Abstract

Hypoxic pulmonary hypertension (PH) can be caused by lung disease, injury, and chronic hypoxia (CH) exposure. Hallmarks for PH include recruitment of immune cells to the perivascular region of the lungs, thickening of the pulmonary arterial walls, elevated pulmonary vascular resistance and pressure, and right ventricular remodeling. These signature signs of PH are what lead to right heart failure and ultimately death. We have previously reported that 21 days of CH leads to both an upregulation of collagen type V (Col V) as well as natural T helper 17 (nTh17) cell-reactivity towards Col V in mouse pulmonary arteries without affecting the number of T regulatory cells (Tregs) in the lungs. However, it is unknown if Treg suppressive capacity and/or peripheral tolerance to autoantigens is affected by CH. Col V-specific Tregs, e.g. peripheral tolerance, can be induced by nasal instillation of Col V without adjuvant. Using right ventricular systolic pressure (RVSP) and pulmonary arterial wall thickening as indicators of PH, we hypothesized that induction of mucosal tolerance to Col V attenuates hypoxic PH in mice. Our data support this hypothesis, as both RVSP and wall thickening are lower in CH-exposed Col V-inoculated vs. vehicle-inoculated mice (Figure). Future studies will characterize the effect of CH on Treg suppressive activity, nTh17 perivascular infiltration, and nTh17-mediated Col V reactivity. In conclusion, our study suggests that induction of mucosal tolerance to Col V attenuates chronic hypoxia-induced PH.