Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.
The combination of physical examination and lymph node US detects the great majority of patients with macroscopic lymph node metastasis (approximately 3% of patients at baseline). Only 10% of patients who have a histologically tumour-positive sentinel node are macroscopically detectable. Altogether, approximately 25% of patients have a positive sentinel node biopsy, among 90% microscopic. The value of whole body staging at baseline remains limited, since distant metastases can hardly ever be detected. The survival benefit of baseline staging and surveillance in patients with cutaneous MM remains to be established by comparative prospective trials.
Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript ( MIAT ) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNA MIAT was identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) and in situ hybridization. Results: Experimental knockdown of MIAT , utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically, MIAT regulated SMC proliferation via the EGR1-ELK1-ERK pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat −/− and Miat −/− ApoE −/− mice as well as Yucatan LDLR −/− mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.
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