Treg Cells Attenuate Pulmonary Venous Remodeling in PH-LHD via NLRC3 Signaling

Gulinigeer Zhakeer; Yanxi Zeng; Guangxi E; Nuerbiyemu Maimaitiaili; Peinan Ju; Hongyun Yao; Yefei Shi; Ming Zhai; Ke Li; Jianhui Zhuang; Yunshan Cao; Qing Yu; Wenhui Peng

doi:10.1161/CIRCRESAHA.124.325201

T_reg Cells Attenuate Pulmonary Venous Remodeling in PH-LHD via NLRC3 Signaling

Circ Res. 2025 May 9;136(10):e113-e128. doi: 10.1161/CIRCRESAHA.124.325201. Epub 2025 Apr 16.

Authors

Gulinigeer Zhakeer^#¹, Yanxi Zeng^#¹, Guangxi E^#¹, Nuerbiyemu Maimaitiaili¹, Peinan Ju¹, Hongyun Yao², Yefei Shi¹, Ming Zhai¹, Ke Li³, Jianhui Zhuang^{1

4}, Yunshan Cao⁵, Qing Yu¹, Wenhui Peng¹

Affiliations

¹ Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China (G.Z., Y.Z., G.E., N.M., P.J., Y.S., M.Z., J.Z., Q.Y., W.P.).
² Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China (H.Y.).
³ Neuroregeneration Key Laboratory of Shanghai Universities, School of Medicine, Tongji University, Shanghai, China (K.L.).
⁴ Department of Cardiology, Shigatse People's Hospital, Tibet, China (J.Z.).
⁵ Heart, Lung and Vessels Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu Sichuan, China (Y.C.).

^# Contributed equally.

PMID: 40235449
DOI: 10.1161/CIRCRESAHA.124.325201

Abstract

Background: Pulmonary venous remodeling is a key pathological feature of pulmonary hypertension associated with left heart disease (PH-LHD). This study aims to investigate the role of regulatory T (T_reg) cells in this process.

Methods: We used mouse models with transverse aortic constriction and cell depletion of Foxp3-DTR/tdTomato mice to examine T_reg cells' function around pulmonary veins in PH-LHD in vivo. To confirm the effect of Nlrc3^-/- T_reg cells on PH-LHD, we utilized 3 mouse models: Nlrc3 knockout mice, athymic mice, and endothelial cell lineage tracing Cdh5CreERT2^+/^--mT/mG^+/^- mice. The interaction proteins and signaling pathways of T_reg cells during endothelial-to-mesenchymal transition were elucidated by protein docking prediction, coimmunoprecipitation and cocultivation of T_reg cells with venous endothelial cells.

Results: T_reg cells were abundant around pulmonary veins of transverse aortic constriction-induced PH-LHD and were essential for promoting inflammation resolution and inhibiting pulmonary venous remodeling. Nlrc3 expression was reduced in mice and patients with PH-LHD. NLRC3 (nucleotide-oligomerization domain-like receptor family CARD domain containing 3) deficiency inhibited T_reg cell proliferation and impaired their immunosuppressive and endothelial-to-mesenchymal transition-protective effects. Mechanistically, NLRC3 interacted with TRAM (TRIF-related adaptor molecule) and regulated interferon regulatory factor 3 (IRF3)/NF-κB (nuclear factor-κB) p65 signaling in cluster differentiation 4⁺ (CD4⁺) T cells. NLRC3-deficient T_reg cells promoted interleukin (IL)-18 expression through IRF3/NF-κB p65 signaling, and thus IL-18 secretion activated endothelial receptor tyrosine kinase (RTK) signaling, favoring endothelial-to-mesenchymal transition progression in pulmonary veins and PH-LHD progress. This process was reversible with IL-18 binding protein in vivo.

Conclusions: NLRC3 is crucial for T_reg cells to prevent pulmonary venous remodeling in PH-LHD, primarily by modulating IL-18 secretion, which inhibits endothelial-to-mesenchymal transition and thereby improves disease progression and prognosis.

Keywords: T-lymphocytes, regulatory; endothelial cells; hypertension, pulmonary; interleukin-18; pulmonary veins.

MeSH terms

Animals
Cells, Cultured
Disease Models, Animal
Female
Humans
Hypertension, Pulmonary* / genetics
Hypertension, Pulmonary* / immunology
Hypertension, Pulmonary* / metabolism
Hypertension, Pulmonary* / pathology
Hypertension, Pulmonary* / physiopathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Veins* / immunology
Pulmonary Veins* / metabolism
Pulmonary Veins* / pathology
Pulmonary Veins* / physiopathology
Signal Transduction
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism
Transcription Factor RelA / metabolism
Vascular Remodeling*

Substances

Transcription Factor RelA