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Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury
Luigi Adamo, … , Deepta Bhattacharya, Douglas L. Mann
Luigi Adamo, … , Deepta Bhattacharya, Douglas L. Mann
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e120137. https://doi.org/10.1172/jci.insight.120137.
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Research Article Cardiology

Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury

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Abstract

Despite the long-standing recognition that the immune response to acute myocardial injury contributes to adverse left ventricular (LV) remodeling, it has not been possible to effectively target this clinically. Using 2 different in vivo models of acute myocardial injury, we show that pirfenidone confers beneficial effects in the murine heart through an unexpected mechanism that depends on cardiac B lymphocytes. Naive hearts contained a large population of CD19+CD11b–CD23–CD21–IgD+IgMlo lymphocytes, and 2 smaller populations of CD19+CD11b+ B1a and B1b cells. In response to tissue injury, there was an increase in neutrophils, monocytes, macrophages, as well as an increase in CD19+ CD11b– B lymphocytes. Treatment with pirfenidone had no effect on the number of neutrophils, monocytes, or macrophages, but decreased CD19+CD11b– lymphocytes. B cell depletion abrogated the beneficial effects of pirfenidone. In vitro studies demonstrated that stimulation with lipopolysaccharide and extracts from necrotic cells activated CD19+ lymphocytes through a TIRAP-dependent pathway. Treatment with pirfenidone attenuated this activation of B cells. These findings reveal a previously unappreciated complexity of myocardial B lymphocytes within the inflammatory infiltrate triggered by cardiac injury and suggest that pirfenidone exerts beneficial effects in the heart through a unique mechanism that involves modulation of cardiac B lymphocytes.

Authors

Luigi Adamo, Lora J. Staloch, Cibele Rocha-Resende, Scot J. Matkovich, Wenlong Jiang, Geetika Bajpai, Carla J. Weinheimer, Attila Kovacs, Joel D. Schilling, Philip M. Barger, Deepta Bhattacharya, Douglas L. Mann

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Figure 1

Effect of pirfenidone on mortality and cardiac myocyte cell death after DT treatment.

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Effect of pirfenidone on mortality and cardiac myocyte cell death after ...
Mice expressing the diphtheria toxin receptor (DTR) in the myocardium were exposed to diphtheria toxin (DT) and fed either chow enriched with pirfenidone (DTR-PFD) or regular chow (DTR-control). (A) Kaplan-Meier survival curves of DTR control and DTR-PFD mice (n = 20 per group). (B) Serum troponin levels measured at day 4 after DT treatment in DTR-PFD and DTR-control animals (n = 23/group). (C) Cardiac myocyte apoptosis measured at day 4 after treatment with DT. Upper panels are representative histological sections of myocardium from DTR-control and DTR-PFD mice at ×40 magnification. Lower panel summarizes the group data (n = 6 mice/group, 4 sections per animal analyzed). (D) Evans blue (EB) dye uptake at day 4 after DT treatment in DTR-control and DTR-PFD animals; upper panels are representative fluorescence microscopy images at ×10 magnification; lower panel summarizes the group data (n = 5 control; n = 6 mice with pirfenidone; 4 sections per animal analyzed). Bars represent the mean, and error bars represent standard deviation. P values were calculated with the Gehan-Breslow-Wilcoxon method for panel A and with Student’s t test for panels B–D.

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