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Appropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/−and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.

HIMF (hypoxia-induced mitogenic factor) is a secreted proinflammatory cytokine with a critical role in cardiac hypertrophy development. Loss of HIMF attenuates transverse aortic constriction-induced cardiac hypertrophy and fibrosis, but the underlying mechanisms are unknown. We show that IL (interleukin)-6 production increases following transverse aortic constriction in wild-type mice; this effect is inhibited in HIMF gene knockout ( Himf −/− ) mice. IL-6 production also increases in cultured cardiac myocytes overexpressing HIMF and neutralizing IL-6 with an anti-IL-6 antibody prohibits HIMF-induced cardiomyocyte hypertrophy. HIMF expression in cardiac fibroblasts cannot be stimulated by transverse aortic constriction or exposure to prohypertrophic factors, including phenylephrine, Ang II (angiotensin II), TGF (transform growth factor)-β, and hypoxia. However, conditioned medium from cardiomyocytes overexpressing HIMF can increase IL-6 production, and cardiac fibroblast proliferation, migration, and myofibroblast differentiation to a similar level as exposure to exogenous rHIMF (recombinant HIMF). Again, neutralizing IL-6 prevented cardiac fibroblasts activation. Finally, the MAPK (mitogen-activated protein kinase) and CaMKII (Ca 2+ /calmodulin-dependent protein kinase II)–STAT3 (signal transducers and activators of transcription 3) pathways are activated in HIMF-overexpressing cardiomyocytes and rHIMF-stimulated cardiac fibroblasts; this effect can be inhibited on neutralizing IL-6. These data support that HIMF induces cardiac fibrosis via a cardiomyocyte-to-fibroblast paracrine effect. IL-6 is a downstream signal of HIMF and has a central role in cardiomyocyte hypertrophy and myocardial fibrosis that is mediated by activating the MAPK and CaMKII-STAT3 pathways.

PurposeEpilepsy is the third most common chronic brain disorder and is characterized by an enduring predisposition for seizures. Recently, a growing body of evidence has suggested that microRNA-146a (miR-146a) is upregulated in the brains of epilepsy patients and of mouse models; furthermore, miR-146a may be involved in the development and progression of seizures through the regulation of inflammation and immune responses. In this report, we performed a case–control study to analyze the relationship between the two potentially functional single nucleotide polymorphisms (SNPs) of the miR-146a gene (rs2910464 and rs57095329) and the risk of epilepsy in a Chinese population comprising 249 cases and 249 healthy controls.MethodOur study comprised 249 epilepsy patients and 249 healthy controls in two regions of China. The DNA was genotyped using the ABI PRISM SNapShot method. The statistical analysis was estimated using the chi-square test or Fisher's exact test.ResultsOur results indicated a significant association between the rs57095329 SNP of the miR-146a gene and the risk of drug resistant epilepsy (DRE) (genotypes, p=0.0258 and alleles, p=0.0108). Moreover, the rs57095329 A allele was found to be associated with a reduced risk of seizures frequency in DRE patients (all p

Introduction Although genetic variants of the A disintegrin and metalloproteinase 10 (ADAM10) gene have been shown to be associated with susceptibility to several inflammatory-related diseases, to date little is known about the clinical relationship in the development of sepsis. Methods Two genetic variants in the promoter of ADAM10 were selected to analyze the potential association with the risk of sepsis. A total of 440 sepsis patients and 450 matched healthy individuals in two independent Chinese Han population were enrolled. Pyrosequencing and polymerase chain reaction-length polymorphism was used to determine the genotypes of the rs514049 and rs653765. A real-time qPCR method was used to detect the mRNA level of ADAM10. Enzyme-linked immunosorbent assay was used to measure the expression levels of substrates CX3CL1, interleukin (IL)-6R, tumor necrosis factor alpha (TNF-α), and the pro-inflammatory cytokines IL-1β and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. Results No statistically significant differences between sepsis cases and controls in the genotype or allele frequencies were observed, suggesting that ADAM10 single nucleotide polymorphisms (SNPs) may not be risk factors for the occurrence of sepsis. A significant difference in the genotype and allele frequencies of the rs653765 SNP between patients with sepsis subtype and severe sepsis (P = 0.0014) or severe sepsis/sepsis shock (P = 0.0037) were observed. Moreover, the rs653765 CC genotype in severe sepsis showed a higher ADAM10 level compared to healthy groups, and the rs653765 CC polymorphism had a strong impact on the production of the ADAM10 substrates CX3CL1, IL-6R and TNF-α. Furthermore, the functional assay showed that ADAM10 C-A haplotype carriers exhibited significantly higher reporter activity compared with the T-A carriers and T-C carriers in human acute monocytic leukemia cell line. Conclusions Our data initially indicated the ADAM10 rs653765 polymorphism was associated with the development of severe sepsis; the risk CC genotype could functionally affect the expression level of ADAM10 mRNA and was accompanied by the up-regulation of its substrates. Thus, ADAM10 might be clinically important and play a critical role in the pathogenesis of the development of sepsis, with potentially important therapeutic implications.