Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

• Published in: American journal of physiology. Heart and circulatory physiology 2009-01, Vol.296 (1), p.H1-H12
• Main Author: Chao, Wei
• Format: Article
• Language: English
• Subjects: Animals; Cardiology; Cardiovascular disease; Cell Survival - physiology; Cells; Heart; Humans; Immunity, Innate - physiology; Infections; Ischemic Preconditioning, Myocardial; Kinases; Myeloid Differentiation Factor 88 - physiology; Myocardial Ischemia - pathology; Myocytes, Cardiac - pathology; Proteins; Review; Signal transduction; Signal Transduction - physiology; Toll-Like Receptors - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00995.2008

Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Submitted 13 September 2008 ; accepted in final form 5 November 2008 ABSTRACT Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart. apoptosis; cardiomyocytes; inflammation; innate immune; interleukin-1 receptor-associated kinase; ischemia-reperfusion; myeloid differentiation primary-response gene 88 adapter-like protein; myocardial infarction; nuclear factor- B; remodeling Address for reprint requests and other correspondence: W. Chao, Dept. of Anesthesia & Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (e-mail: wchao{at}partners.org )