Innate immunity and cardiomyocytes in ischemic heart disease

Abstract

Myocardial ischemia/reperfusion (I/R) is the most common cause of myocardial inflammation, which is primarily a manifestation of the innate immune responses. Innate immunity is activated when pattern recognition receptors (PRRs) respond to molecular patterns common to microbes and to danger signals expressed by injured or infected cells, so called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The expression of various PRRs in cardiomyocytes and the release of DAMPs from cardiomyocytes subjected to I/R injury, through active mechanisms as well as passive processes, enable cardiomyocytes to generate innate immune responses. Studies in isolated heart and cardiomyocytes have confirmed the inflammatory and functional effects of cardiac PRRs especially Toll-like receptors in response to I/R-derived DAMPs, such as heat shock proteins. This review addresses the active role of cardiomyocytes in mediating innate inflammatory responses to myocardial I/R. We propose that cardiomyocytes act as innate immune cells in myocardial I/R injury.

Keywords: Cardiomyocytes; Heart; Inflammation; Innate immunity; Ischemia/reperfusion; NF-κB; Pattern recognition receptor; TLR2; TLR4.

Figure 1

Activation of PPRs in cardiomyocytes by DAMPs during myocardial I/R injury. Cardiomyocytes express a variety of PRRs including transmembrane receptors such as TLRs and CLRs, and cytoplasmic receptors such as NLRs. During myocardial I/R, DAMP molecules including HSP60, HSP72, HSC70 and HMGB1 can be released from ischemic cardiomyocytes, as well as cardiomyocytes undergoing lysis, necrosis and apoptosis. The release of HSP60, HSP72 and HSC70 is dependent on exosomes and/or lipid rafts, but not the classical secretory pathway. All the above DAMPs have been demonstrated to be able to activate TLR4 in cardiomyocytes. HSP72, but not HSP60, were shown to be able to activate TLR2 in cardiomyocytes. The activation of TLR2 and TLR9 by HMGB1 was demonstrated by studies in immune cells, but remains to be examined in cardiomyocytes. Endogenous DAMPs for other TLR subtypes, NLRs and CLRs remain unclear, though their expression has been recognized. The activation of cardiomyocyte TLR4, TLR2 and TLR9 results in NF-kB activation, which subsequently leads to inflammation, cardiac dysfunction and apoptotic effects. The activation of NLRs majorly results in the formation of inflammasome, which activates caspase-1 and trigger inflammation.