Complement Receptor 1 and 2 Deficiency Increases Coxsackievirus B3-Induced Myocarditis, Dilated Cardiomyopathy, and Heart Failure by Increasing Macrophages, IL-1β, and Immune Complex Deposition in the Heart

Abstract

Complement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1β levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220low B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.

Induction of apoptosis by artemisinin relieving the severity of inflammation in caerulein-induced acute pancreatitis

“…Just as the "over-activation of leucocyte theory" proposed by Rindernech et al [27] , AP aggravates because inflammatory cells are over-activated, and these activated cells such as granulocytes and macrophages, play a great role in the development of AP. Therefore, MPO (the marker of neutrophils) and IL-1β (the inflammatory factors generated mainly by mononuclear macrophages) [28] were detected in this study, indicating that MPO is obviously decreased in pancreas tissue after induction of apoptosis, reducing neutrophil recruition and infiltration to pancreas tissue. IL-1β is a kind of proinflammatory cytokines mainly generated by macrophages in pancreas when AP occurs.…”

Autoantibodies in Heart Failure and Cardiac Dysfunction

“…Complement and complement receptors play an important role in both the CVB3-induced and in myosin-induced myocarditis. [27][28][29] ␤1-Adrenoceptor/M2-Receptor ␤1-adrenoceptors (␤1-AR) play an important role in adrenergic regulation of myocardial contractility. They belong to the 7-transmembrane G-protein coupled receptors and stimulation by catecholamines activates the adrenoceptor-adenylylcyclase-protein kinase A cascade (PKA).…”

Autoimmune myocarditis: Past, present and future

“…Noel Rose and his group recently reported, that an adhesive, fibrotic pericarditis is associated with increased DCM and reduced survival in IFN-g deficient mice following Coxsackievirus B3 infection [49]. The development of fibrosis is an important feature in a number of many pathological conditions including myocarditis, and is a key determinant in the clinical outcome of chronic heart disease [49].…”

“…Studies to explore the inductive and the effector mechanisms involved in the development of experimental autoimmune myocarditis (EAM) implicate both innate and adaptive immune responses. Important roles have been shown for autoreactive T cells [35], cardiac-specific autoantibodies [15,19], various cytokines and chemokines [32,[40][41][42][43][44][45][46][47], natural killer cells [11], and the complement system [48,49]. Cunningham and her team recently showed that anti-cardiac myosin antibodies target the beta-adrenergic receptor on the surface of the myocytes and induce cAMP-dependent protein kinase A (PKA) activity in the heart cells [50].…”