Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury
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
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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Research Article Cardiology

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

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 5

Characterization of subsets of myocardial B lymphocytes at baseline and after DT-induced injury and I/R injury.

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Characterization of subsets of myocardial B lymphocytes at baseline and ...
(A) Analysis of subsets of myocardial CD19+ B lymphocytes in naive hearts (n = 4). (B) Mice expressing the diphtheria toxin receptor (DTR) in the myocardium were exposed to diphtheria toxin (DT) and fed either regular chow (control, gray bars) or chow enriched with pirfenidone (PFD, white bars). Mice were sacrificed at day 4 after DT injection and the heart was collected for analysis of myocardial CD19+ B lymphocytes via flow cytometry (n = 4 control, n = 3 pirfenidone). (C) Wild-type mice were subjected to 90 minutes closed-chest ischemia followed by reperfusion (I/R injury). Mice were fed either regular chow (control, gray bars) or chow enriched with pirfenidone (PFD, white bars). Mice were sacrificed at day 4 after I/R injury and the heart was collected for analysis of myocardial CD19+ B lymphocytes via flow cytometry (n = 8 controls, n = 5 pirfenidone). *P < 0.05, **P < 0.01, ***P < 0.001 versus control; †P < 0.001 versus naive hearts. Bars represent the mean, and error bars represent standard deviation. P values were calculated with 2-way ANOVA followed by Tukey’s test for multiple comparisons.