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.

Myocardial B cells are a subset of circulating lymphocytes with delayed transit through the heart

“…This difference could be due to the fact that antibody-mediated B cell depletion causes an acute loss of B cells, whereas μMT mice are deprived of B cells throughout life. Another possible explanation is that μMT mice lack functional B1 cells, whereas antibody-mediated B cell depletion preserves B1 cells (2). It should also be noted that we did not measure the concentration of circulating leukocytes in B cell-deficient/depleted animals and controls.…”

“…Murine myocardium contains BM-derived and non-BM-derived B cells. The murine naive heart harbors a relatively large population of B lymphocytes (2,4,10,11). However, it is not clear whether myocardial B cells are embryonic-derived (non-BM-derived) or derived from the bone marrow (BM).…”

“…B lymphocytes are one of the most prevalent leukocytes in the naive murine heart (1)(2)(3). Prior studies have shown that modulating the number and function of myocardial B cells confers cardioprotective effects in both acute and chronic myocardial injury (2,(4)(5)(6). However, the basic biology of myocardial B cells in the naive heart is unknown.…”

“…This model does not predict that B cells should accumulate in nonlymphoid healthy tissue. Given that B cells play an important role in myocardial injury (2,(4)(5)(6), it is crucial to elucidate the biology of myocardial B cells in the naive state to assess the potential of B cell targeting therapies for cardiac diseases. Here, we investigated the ontogeny, trafficking dynamics, histology, and gene expression profiles of myocardial B cells in order to resolve the apparent inconsistencies between current models of B cell recirculation and the observed populations of B lymphocytes in the naive heart (2)(3)(4)(5)10).…”

Immunomodulatory role of nonneuronal cholinergic signaling in myocardial injury

“…Data are expressed as the percentage area of the myocardium with red fluorescence. Serum troponin I levels were measured by mandibular bleeding on day 3 and 5 after DT injection (38). Troponin levels <0.03 were considered nondetectable.…”