Toll-like receptor 4 stimulation initiates an inflammatory response that decreases cardiomyocyte contractility.
Toll-like receptors (TLRs) have been identified as primary innate immune receptors for the recognition of pathogen-associated molecular patterns by immune cells, initiating a primary response toward invading pathogens and recruitment of the adaptive immune response. TLRs, especially Toll-like receptor 4 (TLR4), can also be stimulated by host-derived molecules and are expressed in the cardiovascular system, thus acting as a possible key link between cardiovascular diseases and the immune system. TLR4 is involved in the acute myocardial dysfunction caused by septic shock and myocardial ischemia. We used wild-type (WT) mice, TLR4-deficient (TLR4-knockout [ko]) mice, and chimeras that underwent myeloablative bone marrow transplantation to dissociate between TLR4 expression in the heart (TLR4-ko/WT) and the immunohematopoietic system (WT/TLR4-ko). Following lipopolysaccharide (LPS) challenge (septic shock model) or coronary artery ligation, myocardial ischemia (MI) model, we found WT/TLR4-ko mice challenged with LPS or MI displayed reduced cardiac function, increased myocardial levels of interleukin-1β and tumor necrosis factor-α, and upregulation of mRNA encoding TLR4 prior to myocardial leukocyte infiltration. The cardiac function of TLR4-ko or WT/TLR4-ko mice was less affected by LPS and demonstrated reduced suppression by MI compared with WT. These results suggest that TLR4 expressed in the cardiomyocytes plays a key role in this acute phenomenon.
Gonda (Goldschmied) Medical Diagnostic Research Center, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Orna
O
Avlas
Reut
R
Fallach
Asher
A
Shainberg
Eyal
E
Porat
Edith
E
Hochhauser
D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D006801:Humans; D007113:Immunity, Innate; D019157:Ischemic Preconditioning, Myocardial; D008070:Lipopolysaccharides / Q000633:toxicity; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4