SUMMARY In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis, while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.

Planar cell polarity (PCP) describes a cell-cell communication process through which individual cells coordinate and align within the plane of a tissue. In this study, we show that overexpression of , a PCP gene, triggers neuronal apoptosis via the dishevelled/Rac1 GTPase/MEKK1/JNK/caspase signalling axis. Consistent with this finding, endogenous expression is upregulated in models of polyglutamine (polyQ) diseases and in fibroblasts from spinocerebellar ataxia type 3 (SCA3) patients. The disruption of this upregulation mitigates polyQ-induced neurodegeneration in We show that the transcriptional regulator Yin Yang 1 (YY1) associates with the promoter. Overexpression of YY1 promotes the hypermethylation of promoter, causing transcriptional repression of Remarkably, YY1 protein is recruited to ATXN3-Q84 aggregates, which reduces the level of functional, soluble YY1, resulting in transcriptional derepression and induction of neuronal apoptosis. Furthermore, transcript level is elevated in amyloid beta-peptide, Tau and α-synuclein models, implicating its potential involvement in other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Taken together, this study unveils a generic Fuz-mediated apoptotic cell death pathway in neurodegenerative disorders.

Many nanoparticle-based carriers to atherosclerotic plaques contain peptides, lipoproteins, and sugars, yet the application of DNA-based nanostructures for targeting plaques remains infrequent. In this work, we demonstrate that DNA-coated superparamagnetic iron oxide nanoparticles (DNA-SPIONs), prepared by attaching DNA oligonucleotides to poly(ethylene glycol)-coated SPIONs (PEG-SPIONs), effectively accumulate in the macrophages of atherosclerotic plaques following an intravenous injection into apolipoprotein E knockout (ApoE −/− ) mice. DNA-SPIONs enter RAW 264.7 macrophages faster and more abundantly than PEG-SPIONs. DNA-SPIONs mostly enter RAW 264.7 cells by engaging Class A scavenger receptors (SR -A) and lipid rafts and traffic inside the cell along the endolysosomal pathway. ABS-SPIONs, nanoparticles with a similarly polyanionic surface charge as DNA-SPIONs but bearing abasic oligonucleotides also effectively bind to SR-A and enter RAW 264.7 cells. Near-infrared fluorescence imaging reveals evident localization of DNA-SPIONs in the heart and aorta 30 min postinjection. Aortic iron content for DNA-SPIONs climbs to the peak (∼60% ID/g) 2 h post-injection (accompanied by profuse accumulation in the aortic root), but it takes 8 h for PEG-SPIONs to reach the peak aortic amount (∼44% ID/g). ABS-SPIONs do not appreciably accumulate in the aorta or aortic root, suggesting that the DNA coating (not the surface charge) dictates in vivo plaque accumulation. Flow cytometry analysis reveals more pronounced uptake of DNA-SPIONs by hepatic endothelial cells, splenic macrophages and dendritic cells, and aortic M2 macrophages (the cell type with the highest uptake in the aorta) than PEG-SPIONs. In summary, coating nanoparticles with DNA is an effective strategy of promoting their systemic delivery to atherosclerotic plaques.

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Aims In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. Methods and results Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. Conclusions Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling.