Whole metagenome analysis has the potential to reveal functional triggers of skin diseases, but issues of cost, robustness and sampling efficacy have limited its application. Here, we have established an alternative, clinically practical and robust metagenomic analysis protocol and applied it to 80 skin microbiome samples epidemiologically stratified for atopic dermatitis (AD). We have identified distinct non-flare, baseline skin microbiome signatures enriched for Streptococcus and Gemella but depleted for Dermacoccus in AD-prone versus normal healthy skin. Bacterial challenge assays using keratinocytes and monocyte-derived dendritic cells established distinct IL-1-mediated, innate and Th1-mediated adaptive immune responses with Staphylococcus aureus and Staphylococcus epidermidis. Bacterial differences were complemented by perturbations in the eukaryotic community and functional shifts in the microbiome-wide gene repertoire, which could exacerbate a dry and alkaline phenotype primed for pathogen growth and inflammation in AD-susceptible skin. These findings provide insights into how the skin microbial community, skin surface microenvironment and immune system cross-modulate each other, escalating the destructive feedback cycle between them that leads to AD flare.
Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins 1 and 5, but not 3, as novel binding partners of AN-GPTL4. ANGPTL4-bound integrin 1 activated the FAKSrc-PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis.
Antimicrobial hydrogels are prepared based on the co‐assembly of commercial Fmoc‐phenylalanine and Fmoc‐leucine, which act as the hydrogelator and antimicrobial building block, respectively. This co‐assembled antimicrobial hydrogel is demonstrated to exhibit selective bactericidal activity for gram‐positive bacteria while being biocompatible with normal mammalian cells, showing great potential as an antimicrobial coating for clinical anti‐infective applications.
A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrinmatrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin-focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.Skin repair after an injury proceeds via a finely tuned pattern of integrated biological events aimed at restoration of the epithelial barrier. The inflammatory stage of repair is followed by the proliferation and migration of keratinocytes, a process called re-epithelialization (1). These events are regulated spatiotemporally by several classical growth factors and cytokines, the effects of which have been well documented (2). Less studied are extracellular factors such as matricellular proteins and adipocytokines, both shown to have a profound local impact during wound repair (3, 4). Effective directed cell migration requires constant cellular interaction with the extracellular matrix (ECM) 3 in response to the changing wound environment. Although the importance of such cell-matrix communication in wound healing is well recognized, the mechanism that modifies the external wound microenvironment for coordinated keratinocyte behavior remains unclear.Integrins on the cell surface often function as biosensors to constantly interrogate the wound environment and modulate cell responses accordingly. Binding of integrins to their cognate matrix proteins activates intracellular signaling pathways that modulate a broad range of cellular processes, including cell migration (5). Integrin-mediated signaling requires that integrins bind substrate-anchored matrix proteins. This interaction provides mechanical resistance that permits tensional forces to be generated via the actomyosin system (6). In contrast, small soluble matrix protein fragments gene...
SummaryBackground Bullous pemphigoid (BP) is the most common autoimmune-mediated subepidermal blistering skin disease and is associated with significant morbidity and mortality. Objectives To determine the 3-year mortality rate, risk factors and causes of death in patients with BP in Singapore, compared with the general population. Methods We conducted a retrospective cohort study of all newly diagnosed patients with BP seen at the National Skin Centre from 1 April 2004 to 31 December 2009. Demographic and clinical data on comorbidities and treatment were recorded. Mortality information was obtained from the National Registry of Diseases. Results In total 359 patients were included in our study. The 1-, 2-, 3-year mortality rates were 26Á7%, 38Á4% and 45Á7%, respectively. The 3-year standardized mortality risk for patients with BP was 2Á74 (95% confidence interval 2Á34-3Á19) times higher than for the age-and sex-matched general population. Parkinson disease, heart failure and chronic renal disease were associated with increased mortality, while combination treatment with low-to-moderate-dose corticosteroids and immunomodulatory agents such as doxycycline and/or nicotinamide was associated with lower mortality. Overall, infections were the most common cause of death (59Á8%), with the main causes of death being pneumonia (42Á7%), cardiovascular disease (14Á6%) and stroke (11Á6%). Conclusions This study confirms an increased 3-year mortality rate for patients with BP in Singapore. Risk factors for increased mortality include medical comorbidities, especially neurological, cardiac and renal diseases. Treatment with combination therapy, including the use of low-to-moderate-dose corticosteroid, appeared to decrease mortality risk in patients with BP.
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