期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 319, 期 6, 页码 L968-L980出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00184.2020
关键词
cellular immunity; gene expression; lung; nT(H)17 cells; pulmonary arterial remodeling
资金
- NIH [T32 HL007736, F30 HL123109, R01 HL132883, R01 AI119140]
- American Heart Association [15GRNT25090039, 18TPA34170037]
- New Mexico IDeA Networks of Biomedical Research Excellence (NMINBRE) through the National Institute of General Medical Sciences IDe-Award [P20GM103451]
Chronic hypoxia (CH)-induced pulmonary hypertension (PH) results, in part, from T helper-17 (T(H)17) cell-mediated perivascular inflammation. However, the antigen(s) involved is unknown. Cellular immunity to collagen type V (col V) develops after ischemia-reperfusion injury during lung transplant and is mediated by naturally occurring (n)T(H)17 cells. Col5a1 gene codifies for the alpha 1-helix of col V, which is normally hidden from the immune system within type I collagen in the extracellular matrix. COL5A1 promoter analysis revealed nuclear factor of activated T cells, cytoplasmic 3 (NFATc3) binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates col V expression, leading to nT(H)17 cell-mediated autoimmunity to col V in response to CH, representing an upstream mechanism in PH development. To test our hypothesis, we measured indexes of PH in inducible smooth muscle cell (SMC)-specific NFATc3 knockout (KO) mice exposed to either CH (380 mmHg) or normoxia and compared them with wild-type (WT) mice. KO mice did not develop PH. In addition, COL5A1 was one of the 1,792 genes differentially affected by both CH and SMC NFATc3 in isolated intrapulmonary arteries, which was confirmed by RT-PCR and immunostaining. Cellular immunity to col V was determined using a trans vivo delayed-type hypersensitivity assay (Tv-DTH). Tv-DTH response was evident only when splenocytes were used from control mice exposed to CH but not from KO mice, and mediated by nT(H)17 cells. Our results suggest that SMC NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen COL5A1 protein contributing to col V-reactive nT(H)17-mediated inflammation and hypertension.
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