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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 4

Effect of pirfenidone on myocardial inflammation (day 4) after I/R injury.

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Effect of pirfenidone on myocardial inflammation (day 4) after I/R injur...
Wild-type mice were subjected to 90 minutes closed-chest ischemia followed by reperfusion (I/R injury). Mice were fed either chow enriched with pirfenidone (PFD) or regular chow. Mice were sacrificed at day 4 after I/R injury and the heart was collected for analysis via flow cytometry. n = 8 I/R-control, n = 4 I/R-PFD. (A) Total number of CD45+ cells/mg heart tissue. (B) Leukocyte subsets in the myocardium (percentage of total: CD19+, Ly6g+, Ly6C+CD64lo/–, CD64+Ly6Clo; n = 4/group). (C) Representative FACS analysis of MHC-II and CCR-2 macrophages and monocytes. (D) Macrophage/monocyte subsets in the myocardium as defined by expression of CCR 2, low (l) or high (h) and MHC-II expression, low (l) or high (h). Percentage of total, n = 4/group.***P < 0.001. Bars represent the mean, and error bars represent standard deviation. P values were calculated with Student’s t test.

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