Biology subjects

Lal, H.

Publications and source records attributed to Lal, H..

2 recordsLinked to original sources

bioRxiv2019

CADHERIN-11 BLOCKADE REDUCES INFLAMMATION DRIVEN FIBROTIC REMODELING AND IMPROVES OUTCOMES AFTER MYOCARDIAL INFARCTION

BackgroundOver one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not yet been studied in the context of cardiac remodeling after MI. We hypothesized that targeting CDH11 function after MI would reduce inflammation-driven fibrotic remodeling and infarct expansion to improve functional outcomes in mice. MethodsMI was induced by ligation of the left anterior descending artery in transgenic mice with reduced or ablated CDH11, wild type mice receiving bone marrow transplants from Cdh11 transgenic animals, and wild type mice treated with a functional blocking antibody against CDH11 (SYN0012). Cardiac function was measured by echocardiography, expression of cell populations was quantified by flow cytometry, and tissue remodeling by altered histological assessment and transcription of inflammatory and pro-angiogenic genes by qPCR. Co-culture was used to assess interactions between cardiac fibroblasts and macrophages. ResultsMI increased transcription of Cdh11 in non-cardiomyocyte cells. Mice with deletion of Cdh11 and wild type mice receiving bone marrow transplants from Cdh11 transgenic animals had improved cardiac function and dimensions after MI. Animals given SYN0012 had improved cardiac function, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 also reduced the number of bone marrow-derived myeloid cells and increased pro-angiogenic cells in the heart three days after MI, consistent with a decrease in transcription and expression of IL-6 in the infarct region. Cardiac fibroblast and macrophage interactions led to an increase in IL-6 secretion that was reduced with SYN0012 treatment in vitro. ConclusionsOur findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI, and that targeting CDH11 with a blocking antibody improves cardiac function after MI. This improvement is likely mediated by altered recruitment of bone marrow-derived cells, thereby limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.

molecular biology↗

bioRxiv2019

IL-10-producing B cells are enriched in murine pericardial adipose tissues and ameliorate the outcome of acute myocardial infarction

Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate repair. However, exaggerated and/or persistent inflammation compromises healing, which may be counteracted by regulatory immune mechanisms. A key regulatory factor in an inflammatory response is the anti-inflammatory cytokine IL-10, which can be produced by a number of immune cells including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found abundant IL-10-producing B cells in PATs under homeostatic conditions, with the majority of them bearing cell surface CD5 (CD5+ B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters (FALCs). The cytokine IL-33 was preferentially expressed in PATs under homeostatic conditions and contributed to enrichment of IL-10-producing CD5+ B cells in PATs. CD5+ B cells expanded in PATs following MI, and accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function after MI, exacerbated myocardial injury, and delayed resolution of inflammation. These findings reveal a significant contribution of IL-10-producing B cells to the anti-inflammatory mechanism that terminates MI-induced inflammation, and identify these cells as novel therapeutic targets to improve the outcome of MI. Significance StatementMyocardial infarction (MI) remains a leading cause of mortality and morbidity worldwide. Although it is now recognized that a balanced and timely terminated pro-inflammatory response following acute MI is essential in promoting tissue repair, the underlying regulatory mechanisms are poorly defined. In this report, we show that IL-10-producing B cells in mice 1) are enriched in pericardial adipose tissues (PATs) and influenced by cytokine IL-33 under homeostatic conditions; 2) expand in PATs following MI and accumulate in the infarcted heart during the resolution of MI-induced inflammation; and 3) facilitate resolution of inflammation and reduce myocardial injury to preserve cardiac function after MI. These findings identify IL-10-producing B cells as novel therapeutic targets to improve the outcome of MI.

immunology↗