Role of cardiac- and myeloid-MyD88 signaling in endotoxin shock: a study with tissue-specific deletion models.

BACKGROUND Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critical for host innate immunity. Studies have shown that signaling via MyD88 contributes to cytokine storm, cardiac dysfunction, and high mortality during endotoxin shock.However, the specific contribution of MyD88 signaling of immune and cardiac origins to endotoxin shock remains unknown. METHODS Tissue-specific MyD88 deletion models: Cre-recombinase transgenic mice with α-myosin heavy chain (α-MHC) or lysozyme M promoters were cross-bred with MyD88-loxP (MyD88fl/fl) mice, respectively, to generate cardiomyocyte- (α-MHCMyD88−/−) or myeloid-specific (Lyz-MyD88−/−) MyD88 deletion models and their respective MyD88fl/fl littermates. Endotoxin shock model: Mice were subjected to 15 mg/kg lipopolysaccharide (intraperitoneal injection). Cardiac function was measured by echocardiography and cytokines by multiplex assay and quantitative reverse transcription-polymerase chain reaction. RESULTS α-MHC-MyD88−/− mice had 61 and 87% reduction in MyD88 gene and protein expression in cardiomyocytes,respectively, whereas Lyz-MyD88−/− had 73 and 67% decrease, respectively, in macrophages (n=3 per group). After lipopolysaccharide treatment, the two groups of MyD88fl/fl littermates had 46% (n=10) and 60% (n=15) of mortality, respectively.Both α-MHC-MyD88−/− and Lyz-MyD88−/− mice had markedly improved survival. Compared with the MyD88fl/fl littermates, Lyz-MyD88−/− mice had warmer body temperature, attenuated systemic and cardiac inflammatory cytokine production,and significantly improved cardiac function, whereas α-MHC-MyD88−/− mice had decreased myocardial inducible nitricoxide synthase induction and modestly preserved cardiac function. CONCLUSIONS Both cardiomyocyte- and myeloid-MyD88 signaling play a role in cardiac dysfunction and mortality during endotoxin shock. Myeloid-MyD88 signaling plays a predominant role in systemic and cardiac inflammation after endotoxin challenge.