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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 6

Effect of B cell depletion on pirfenidone cardioprotective effect after I/R injury.

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Effect of B cell depletion on pirfenidone cardioprotective effect after ...
Wild-type mice were B cell depleted via injection of anti-CD20 antibody. Seven days after injection of anti-CD20 antibody, B cell–depleted mice were subjected to 90 minutes of closed-chest ischemia followed by reperfusion (I/R injury). Mice were fed either chow enriched with pirfenidone (anti-CD20 PFD) or regular chow (anti-CD20 control). (A) Area at risk during closed chest-ischemia as determined by the simplified segmental wall motion score index (SWMSI) at time of ischemia. (B) Representative pictures of hearts harvested from anti-CD20–treated mice (left) and anti-CD20 + pirfenidone–treated animals (right). Scale bar: 1 mm. (C) Gravimetric analysis of hearts harvested from pirfenidone-treated animals (anti-CD20 PFD) and untreated controls (anti-CD20 control), n = 7/group. (D–F) Echocardiographic assessment of myocardial function at the time of ischemia and 2 weeks after I/R injury, n = 7/group. Data from non–anti-CD20–treated animals already reported in Figure 3, D–F are shown again for comparison only (control). (D) Left ventricular (LV) mass (LVM) by 2-D echocardiography. (E) LV end-diastolic volume (LVEDV). (F) LV ejection fraction (LVEF). (G) Representative trichrome staining of histological sections of hearts from control animals (left panel) and pirfenidone-treated animals (right panel). Original magnification, ×1.25. (H) Quantitative assessment of the percentage of trichrome-positive staining, 2 sections analyzed per heart, n = 10 sections/group. Bars represent the mean, and error bars represent standard deviation. P values were calculated with Student’s t test.

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