TY - JOUR
T1 - Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury
AU - Adamo, Luigi
AU - Staloch, Lora J.
AU - Rocha-Resende, Cibele
AU - Matkovich, Scot J.
AU - Jiang, Wenlong
AU - Bajpai, Geetika
AU - Weinheimer, Carla J.
AU - Kovacs, Attila
AU - Schilling, Joel D.
AU - Barger, Philip M.
AU - Bhattacharya, Deepta
AU - Mann, Douglas L.
PY - 2018/6/7
Y1 - 2018/6/7
N2 - 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.
AB - 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.
KW - B cells
KW - Cardiology
KW - Heart failure
UR - http://www.scopus.com/inward/record.url?scp=85062248482&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062248482&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.120137
DO - 10.1172/jci.insight.120137
M3 - Article
C2 - 29875326
AN - SCOPUS:85062248482
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 11
ER -