Th9-arterial endothelial cell crosstalk promotes psoriatic atherosclerosis

Ishita Baral, Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Yvonne Baumer, Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Aarohan Mukerjhee Burma, Graduate Division, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
McKella Sylvester, Department of Graduate Medical Education, Alabama College of Osteopathic Medicine, Dothan, AL, USA.
Kyle Jones, Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Moses Mwesigwa Kitakule, School of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Amit Dey, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
Justin Rodante, Laboratory of Heart Disease Phenomics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Cristhian A. Gutierrez-Huerta, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Bhavani Taramangalam, Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Julio Diaz Perez, Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
Liang Guo, Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gaithersburg, MD, USA.
Alyssa Grogan, CVPath Institute, Gaithersburg, MD, USA.
Tatsuya Shiraki, CVPath Institute, Gaithersburg, MD, USA.
Aloke V. Finn, CVPath Institute, Gaithersburg, MD, USA; School of Medicine, University of Maryland, Baltimore, MD, USA.
Aran Son, Neuroscience Area, International School for Advanced Studies (SISSA), Trieste, Italy.
Kyoungin Cho, Mouse Genetics and Gene Modification Section, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Jaspal S. Khillan, Mouse Genetics and Gene Modification Section, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Marcus Y. Chen, Cardiovascular Computed Tomography Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Tiffany M. Powell-Wiley, Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Intramural Research Program, National Institute on Minority Health and Health Disparities, NIH, Bethesda, MD, USA.
Pamela A. Frischmeyer-Guerrerio, Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Joshua D. Milner, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
Nehal N. Mehta, Departments of Medicine and Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Guido H. Falduto, Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Daniella M. Schwartz, Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: Daniella.Schwartz@pitt.edu.

Document Type

Journal Article

Publication Date

12-12-2025

Journal

Annals of the rheumatic diseases

DOI

10.1016/j.ard.2025.11.008

Abstract

OBJECTIVES: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD. METHODS: Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE, IL-23-ApoE, and Card14-ApoE) were investigated using IL-9 blockade or global and endothelial-specific Il9r deletion. Primary human aortic endothelial cells were used to assess IL-9/STAT3-dependent endothelial responses. RESULTS: Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants. CONCLUSIONS: These findings suggest the Th9 state may represent a novel psoriatic ASCVD endotype that could be targeted using precision approaches to prevent ASCVD in at-risk individuals.

Department

Medicine

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