B Lymphocytes: Adding Insult to Injury After Myocardial Infarction

Acute myocardial infarction (MI) is typically caused by an abrupt blockage of a coronary artery, leading to necrosis of the affected heart tissue. Immediately afterward, distinct leukocyte cell populations— predominantly neutrophils, lymphocytes, and monocytes—infiltrate the injured heart. This inflammation ultimately leads to fibrosis of the affected tissue, a process termed "remodeling." The long-term effect of an MI can vary in humans, even for the same size infarct: Some patients regain near-normal cardiac function, whereas others experience progressive heart failure. The mechanisms underlying these variable responses are incompletely understood, although so-called Ly6Chi monocytes are known to be particularly maladaptive in mouse models of MI. Zouggari and colleagues have now investigated how monocytes are recruited to myocardial tissue after an infarct. Their results implicate the chemokine CCL7, secreted by a subset of mature B2 lymphocytes, as the obligate upstream event that triggers Ly6Chi monocyte influx and the consequent impairment of cardiac function. The authors first depleted B2 cells and tested the resulting effect on infarct size, inflammatory mediators, and cardiac function in a mouse model of acute MI. They achieved B2 cell deletion in three ways: (i) treatment with antibodies to CD20, (ii) genetic deletion of the receptor for B-cell activating factor (Baff), or (iii) inhibition with Baff antibodies. B cell depletion blunted the inflammatory response, reduced infarct size, and preserved cardiac function, as assessed with echocardiography. Also apparent was impaired monocyte mobilization from the bone marrow to the blood and less macrophage accumulation within the infarcted hearts. To investigate how B cells regulate monocyte trafficking, a process known to involve the chemokine receptor CCR2, the authors measured the expression of this receptor’s endogenous ligands CCL2 and CCL7. They found that CCL7 was particularly responsive to B cell depletion. The authors next presented a series of elegant in vivo experiments in which the cardioprotective effect of B cell depletion was reversed through reintroduction of wild-type B cells, but not if those B cells were CCL-7–deficient. Thus, the authors conclude that B cells contribute to pathologic remodeling of the heart by virtue of their capacity for CCL7 expression, which leads to monocyte recruitment from the bone marrow to the injured heart. Last, in a human cohort of patients with acute MI, patients with detectable CCL7 had increased risk of recurrent MI or death as compared with patients with undetectable CCL7. These data suggest that pathologic remodeling after MI requires signaling by B2 lymphocytes, which direct monocyte recruitment from the bone marrow to the heart through a mechanism requiring CCL-7. This finding is significant and unexpected because the trafficking of B cells to the heart is diminutive and delayed compared with other leukocyte cell types typically implicated in postinfarction cardiac inflammation. Cardiac remodeling after MI may be as much a systemic process as a local one. Whether these inflammatory processes can be targeted to improve outcomes after MI in humans remains to be seen. However, since effective anti–B cell therapies are already approved for rheumatoid arthritis, clinical trials to explore a pathologic role for B cells after MI may be feasible with existing biological therapies. Y. Zouggari et al ., B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat. Med. , published online 15 September 2013 (10.1038/nm.3284). [[Abstract]][1] [1]: http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3284.html