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Ischemic injury initiates a sterile inflammatory response that ultimately participates in the repair and recovery of tissue perfusion. Macrophages are required for perfusion recovery during ischemia, in part because they produce growth factors that aid in vascular remodeling. The input signals governing this pro-revascularization phenotype remain of interest. Here we found that hindlimb ischemia increases levels of resolvin D1 (RvD1), an inflammation-resolving lipid mediator that targets macrophages via its receptor, ALX/FPR2. Exogenous RvD1 enhances perfusion recovery during ischemia, and mice deficient in Alx/Fpr2 have an endogenous defect in this process. Mechanistically, RNA sequencing revealed that RvD1 induces a transcriptional program in macrophages characteristic of a pro-revascularization phenotype. Vascularization of ischemic skeletal muscle, as well as cutaneous wounds, is impaired in mice with myeloid-specific deficiency of Alx/Fpr2 , and this is associated with altered expression of pro-revascularization genes in skeletal muscle and macrophages isolated from skeletal muscle. Collectively, these results uncover a role of ALX/FPR2 in revascularization that may be amenable to therapeutic targeting in diseases associated with altered tissue perfusion and repair.

Muscle damage elicits a sterile immune response that facilitates complete regeneration. Here, we used mass spectrometry-based lipidomics to map the mediator lipidome during the transition from inflammation to resolution and regeneration in skeletal muscle injury. We observed temporal regulation of glycerophospholipids and production of pro-inflammatory lipid mediators (for example, leukotrienes and prostaglandins) and specialized pro-resolving lipid mediators (for example, resolvins and lipoxins) that were modulated by ibuprofen. These time-dependent profiles were recapitulated in sorted neutrophils and Ly6Chi and Ly6Clo muscle-infiltrating macrophages, with a distinct pro-resolving signature observed in Ly6Clo macrophages. RNA sequencing of macrophages stimulated with resolvin D2 showed similarities to transcriptional changes found during the temporal transition from Ly6Chi macrophage to Ly6Clo macrophage. In vivo, resolvin D2 increased Ly6Clo macrophages and functional improvement of the regenerating muscle. These results reveal dynamic lipid mediator signatures of innate immune cells and provide a proof of concept for their exploitable effector roles in muscle regeneration.

In the version of this article initially published, two arrows in the far right plot of Fig. 3c were aimed incorrectly, and the error bars were missing in Fig. 6e,f. In Fig. 3c, the arrow labeled '5-LOX' should be aimed at the plot measuring LXB4, and the arrow labeled 'LTA4H' should be aimed at the plot measuring LTB4. The errors have been corrected in the HTML and PDF versions of the article.

The infiltration and subsequent in situ subtype specification of monocytes to effector/inflammatory and repair macrophages is indispensable for tissue repair upon acute sterile injury. However, the chromatin-level mediators and regulatory events controlling this highly dynamic macrophage phenotype switch are not known. In this study, we used a murine acute muscle injury model to assess global chromatin accessibility and gene expression dynamics in infiltrating macrophages during sterile physiological inflammation and tissue regeneration. We identified a heme-binding transcriptional repressor, BACH1, as a novel regulator of this process. Bach1 knockout mice displayed impaired muscle regeneration, altered dynamics of the macrophage phenotype transition, and transcriptional deregulation of key inflammatory and repair-related genes. We also found that BACH1 directly binds to and regulates distal regulatory elements of these genes, suggesting a novel role for BACH1 in controlling a broad spectrum of the repair response genes in macrophages upon injury. Inactivation of heme oxygenase-1 (Hmox1), one of the most stringently deregulated genes in the Bach1 knockout in macrophages, impairs muscle regeneration by changing the dynamics of the macrophage phenotype switch. Collectively, our data suggest the existence of a heme–BACH1­–HMOX1 regulatory axis, that controls the phenotype and function of the infiltrating myeloid cells upon tissue damage, shaping the overall tissue repair kinetics.

Skeletal muscle regeneration following injury is a complex process that involves inflammatory components. Macrophage infiltration to damaged tissues upon injuries and their in-situ differentiation ...

LHC@home has provided computing capacity for simulations under BOINC since 2005. Following the introduction of virtualisation with BOINC to run HEP Linux software in a virtual machine on volunteer desktops, initially started on test BOINC projects, like Test4Theory and ATLAS@home, all CERN applications distributed to volunteers have been consolidated under a single LHC@home BOINC project. As part of an effort to unite CERN’s batch, cloud, grid and volunteer computing efforts, the BOINC service has been integrated with the other compute services at CERN, notably HTCondor, in terms job submission and accounting. The paper will also address contributions to improve the BOINC software and community effort to evolve BOINC for a sustainable volunteer computing environment. Furthermore, we discuss future challenges to reduce the effort required by volunteers to run virtual machines for experiment simulations and improvements to BOINC to widen the appeal of volunteer computing.

MicroRNAs are important components of the post-transcriptional fine-tuning of macrophage gene expression in physiological and pathological conditions. However, the mechanistic underpinnings and the cis-acting genomic factors of how macrophage polarizing signals induce miRNA expression changes are not well characterized. Therefore, we systematically evaluated the transcriptional basis underlying the inflammation-mediated regulation of macrophage microRNome using the combination of different next generation sequencing datasets. We investigated the LPS-induced expression changes at mature miRNA and pri-miRNA levels in mouse macrophages utilizing a small RNA-seq method and publicly available GRO-seq dataset, respectively. Next, we identified an enhancer set associated with LPS-responsive pri-miRNAs based on publicly available H3K4 mono-methylation-specific ChIP-seq and GRO-seq datasets. This enhancer set was further characterized by the combination of publicly available ChIP and ATAC-seq datasets. Finally, direct interactions between the miR-155-coding genomic region and its distal regulatory elements were identified using a 3C-seq approach. Our analysis revealed 15 robustly LPS-regulated miRNAs at the transcriptional level. In addition, we found that these miRNA genes are associated with an inflammation-responsive enhancer network. Based on NFκB-p65 and JunB transcription factor binding, we showed two distinct enhancer subsets associated with LPS-activated miRNAs that possess distinct epigenetic characteristics and LPS-responsiveness. Finally, our 3C-seq analysis revealed the LPS-induced extensive reorganization of the pri-miR-155-associated functional chromatin domain as well as chromatin loop formation between LPS-responsive enhancers and the promoter region. Our genomic approach successfully combines various genome-wide datasets and allows the identification of the putative regulatory elements controlling miRNA expression in classically activated macrophages.