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 8

H/L-induced CD4+ T cell UPR dysregulation is dependent on the microenvironment.

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H/L-induced CD4+ T cell UPR dysregulation is dependent on the microenvir...
WT mice were fed STD, H/L, or H/L for 5 weeks and then STD for 2 weeks (H/L->S) prior to analysis (A). (B and C) Ejection fraction in these mice was measured by echocardiography. (D and E) Splenic CD4+ T cells were isolated from mice in each group and measured for Xbp1s expression by qPCR (D), and systolic blood pressure (SBP; E) was measured by invasive hemodynamic analysis. (F) LV from mice in each group was weighed and normalized to tibia length (LV/TL). (G and H) In mice from these groups, in addition to a cohort of mice fed H/L for 5 weeks then reverted to STD for 3 weeks, end-diastolic pressure–volume relationship (EDPVR) was quantified by invasive hemodynamic analysis (G), and cardiac CD45+CD3+CD4+ cells were analyzed in LV of mice from each group directly by flow cytometry (H). n = 3–12. Error bars represent the mean ± SEM. One-way ANOVA with Tukey’s multiple-comparison test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. This figure was created using Biorender.com.