The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6C^lo macrophages toward increased numbers of inflammatory Ly6C^hi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6C^hi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.

Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 on MI healing. Ischemia/reperfusion (I/R) injury was induced in mice and Wnt signaling was inhibited by oral administration of the porcupine inhibitor LGK-974. The transcriptome was analyzed from infarcted tissue by using RNA sequencing analysis. The inflammatory response after I/R was evaluated by flow cytometry. Heart function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Transcriptome and gene set enrichment analysis revealed a modulation of the inflammatory response upon administration of the Wnt secretion inhibitor LGK-974 following I/R. In addition, LGK-974-treated animals showed an attenuated inflammatory response and improved heart function. In an in vitro model of hypoxic cardiomyocyte and monocyte/macrophage interaction, LGK974 inhibited the activation of Wnt signaling in monocytes/macrophages and reduced their pro-inflammatory phenotype. We here show that Wnt signaling affects inflammatory processes after MI. The Wnt secretion inhibitor LGK-974 appears to be a promising compound for future immunomodulatory approaches to improve cardiac remodeling after MI.

Highly pathogenic influenza A virus H5 subtype remains a risk for transmission in humans. The H5N8 subtype has caused multiple outbreaks in poultry in Europe over the past few winters. During one recent outbreak in poultry in Astrakhan, workers on the farm were also infected. So far, little is known about how this virus evolves and adapts to infect humans. Here, we performed a time-resolved phylogenetic analysis of 129 HA sequences representing all 1891 available H5N8 viruses collected from 2010 to 2020. We also conducted a whole-genome scan on the human virus at the protein level. We found that H5N8 viruses have spilled over in 34 European countries during the flu season of 2020–2021. These viruses underwent two significant evolutionary steps during 2015–2016 and after 2018. Furthermore, we characterized a number of critical mutations in all viral proteins except PB1-F2, which contribute to increased virulence and avian-to-human adaptation. Our findings suggested that the accumulated mutations under evolution led to quantitative and qualitative changes, likely allowing the virus to spread to humans. Given that the H5N8 virus is co-circulating with other H5 viruses in Europe, the risk of a pandemic should not be underestimated. Continental surveillance and pandemic preparedness are to be established.

The coronavirus (COVID-19) pandemic has been a global threat for the past three years at the time of writing, leading to more than 675 million confirmed cases and 6