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

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

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

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Figure 5

H/L induces dysregulation of T cell UPR gene expression.

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H/L induces dysregulation of T cell UPR gene expression. (A) UPR activit...
(A) UPR activity can be measured by the gene and protein expression of sensors in the ER lumen and downstream effector proteins. (B and C) The protein expression and activation of each UPR sensor was analyzed by Western blotting in splenic CD4+ T cells from mice fed H/L or STD for 5 weeks. (D) Spliced and unspliced Xbp1 expression was analyzed using semiquantitative PCR and horizontal gel electrophoresis in splenic CD4+ T cells from mice fed H/L or STD for 5 weeks. (E–G) The expression of the XBP1s gene targets Dnajb9, Sec63, and Sec24d was analyzed by quantitative PCR (qPCR) in splenic CD4+ T cells from mice fed H/L or STD for 5 weeks. (H–J) The gene expression of Xbp1s, Atf6, and Atf4 was analyzed by qPCR in splenic CD4+ T cells from mice fed H/L or STD for 1, 3, or 5 weeks (H), and cardiac CD45+CD3+CD4+ cells were analyzed by flow cytometry (I and J). (K) Qualitative representation of splenic CD4+ T cell Xbp1s expression and cardiac CD4+ T cell infiltration in mice fed H/L demonstrates an inverse correlation. B and C: Each replicate is n = 4 mice pooled, and molecular weights are listed next to blots. C: The normalized expression of each protein is represented as a fold change relative to STD control. D–J: n = 5–11. Error bars represent the mean ± SEM. C and E–G: Unpaired, 2-tailed t test; H–J: H/L group from each time point is compared against its respective STD control in unpaired, 2-tailed t test, and 1- and 3-week time points are plotted against 5-week data from Figure 1 and Figure 4. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. This figure was created using Biorender.com.