Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling.

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Myocardial infarction (MI) is the leading cause of death in Western countries. Epidemiological studies show acute MI to be more prevalent in the morning and to be associated with a poorer outcome in terms of mortality and recovery. The mechanisms behind this association are not fully understood. Here, we report that circadian oscillations of neutrophil recruitment to the heart determine infarct size, healing, and cardiac function after MI. Preferential cardiac neutrophil recruitment during the active phase (Zeitgeber time, ZT13) was paralleled by enhanced myeloid progenitor production, increased circulating numbers of CXCR2hi neutrophils as well as upregulated cardiac adhesion molecule and chemokine expression. MI at ZT13 resulted in significantly higher cardiac neutrophil infiltration compared to ZT5, which was inhibited by CXCR2 antagonism or neutrophil‐specific CXCR2 knockout. Limiting exaggerated neutrophilic inflammation at this time point significantly reduced the infarct size and improved cardiac function.

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Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF) which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacologic experiments. The pharmacovigilance database, VigiBase ® was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for four weeks results in inducible AF, left atrial enlargement, myocardial fibrosis and inflammation. This effect was reproduced in mice lacking BTK but not in mice treated with four-weeks of acalabrutinib, a more specific BTK inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving C-terminal src kinase (CSK) as the strongest candidate for ibrutinib induced AF. Cardiac specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in Vigibase ® confirmed increased reporting of AF associated with kinase inhibitors blocking Csk vs non-Csk inhibitors, with a reporting odds-ratio of 8.0 [95% CI 7.3-8.7, p<0.0001]. Conclusions: These data identify Csk inhibition as the mechanism by which ibrutinib leads to AF. Clinical Trial Registration: URL: www.clinicaltrials.gov Unique Identifier: NCT03530215

Highlights d Gene expression profiling mapped systemic macrophage responses to sepsis, MI, and stroke d The tissue microenvironment determined phenotypic adaptions following remote injury d Local proliferation dominated over recruitment in expanding tissue macrophage numbers d Alveolar macrophage priming post MI increased resilience against subsequent pneumonia

Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating evidence indicates that these risk factors may fuel chronic inflammatory processes that are active in atherosclerosis and lead to myocardial infarction and stroke. In concert with hyperlipidemia, maladaptive immune system activities can contribute to disease progression and increase the probability of adverse events. In this review, we discuss recent insight into how the above modifiable risk factors influence innate immunity. Specifically, we focus on pathways that raise systemic myeloid cell numbers and modulate immune cell phenotypes, reviewing hematopoiesis, leukocyte trafficking, and innate immune cell accumulation in cardiovascular organs. Often, relevant mechanisms that begin with lifestyle choices and lead to cardiovascular events span multiple organ systems, including the central nervous, endocrine, metabolic, hematopoietic, immune and, finally, the cardiovascular system. We argue that deciphering such pathways provides not only support for preventive interventions but also opportunities to develop biomimetic immunomodulatory therapeutics that mitigate cardiovascular inflammation.

Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction, and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.