Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction

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Abstract

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1α/X-box–binding protein 1 (IRE1α/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1α/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1α/XBP1 axis was a T cell signature of HFpEF.

Authors

Sasha Smolgovsky, Abraham L. Bayer, Kuljeet Kaur, Erin Sanders, Mark Aronovitz, Mallory E. Filipp, Edward B. Thorp, Gabriele G. Schiattarella, Joseph A. Hill, Robert M. Blanton, Juan R. Cubillos-Ruiz, Pilar Alcaide