2019.05.31

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Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis.

Williams MR1, Costa SK2, Zaramela LS3, Khalil S1, Todd DA4, Winter HL4, Sanford JA1, O’Neill AM1, Liggins MC1, Nakatsuji T1, Cech NB4, Cheung AL2, Zengler K3,5,6, Horswill AR7,8, Gallo RL9,5.

Abstract

Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides’ capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus-mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.

2019_05_31

2019_05_31_SS

2019-05-24 Journal Club

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2019 May 14. doi: 10.1111/all.13870. [Epub ahead of print]

Pruritus in ordinary scabies: IL-31 from macrophages induced by overexpression of TSLP and periostin.

Hashimoto T1,2, Satoh T2, Yokozeki H1.

Abstract

BACKGROUND:

Scabies is a common contagious skin disease caused by an infestation of the skin by Sarcoptes scabiei var. hominis. A hallmark symptom of scabies is severe itch.

METHODS:

We sought to determine the generation of a pruritogenic cytokine, interleukin (IL)-31, together with immune profiles in skin lesions of ordinary scabies through immunohistochemical and immunofluorescent studies. To elucidate the pathological mechanisms of IL-31 generation, murine peritoneal macrophages were stimulated with various T helper 2 (Th2) cytokines and proteins ex vivo.

RESULTS:

A large number of CCR4(+) Th2 cells, eosinophils, and basophils infiltrated in scabies lesions. Increased generation of IL-31, TSLP, and periostin was also observed. A major population of IL-31(+) cells were Arginase-1(+)/CD163(+) M2 macrophages. Murine peritoneal macrophages showed an M2 phenotype and generated IL-31 when stimulated with TSLP and periostin.

CONCLUSION:

IL-31 appeared to be largely generated by M2 macrophages in ordinary scabies lesions. This IL-31 induction was mediated by TSLP and periostin. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

TSLP ; IL-31; macrophage; periostin; scabies

Journal Club 19.05.10.

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The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels

The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels

Sara Baratchi1*, Peter Keov1,2,3, William G. Darby1, Austin Lai1, Khashayar Khoshmanesh4, Peter Thurgood4, Parisa Vahidi1, Karin Ejendal5 and Peter McIntyre1
1 School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia, 2 Molecular Pharmacology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia, 3 St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia, 4 School of Engineering, RMIT University, Melbourne, VIC, Australia, 5 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States

TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.
Keywords: TRPV4, membrane trafficking, endothelial cells, GSK1016790A, calcium

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