Isotretinoin is indirectly effective in sebocytes

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Primary alterations during the development of hidradenitis suppurativa

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine gland‐rich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin. OBJECTIVES: We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, non‐lesional HS and lesional HS skin, with the parallel application of multiple mRNA and protein‐based methods. METHODS: Immune cell counts (T cells, dendritic cells, macrophages), Th1/Th17‐related molecules (IL‐12B, TBX21, IFNG, TNFA, IL‐17, IL10, IL‐23A, TGFB1, RORC, CCL20), keratinocyte‐related sensors (TLR2,4), mediators (S100A7, S100A8, S100A9, DEFB4B, LCN2, CAMP, CCL2) and pro‐inflammatory molecules (IL1B, IL6, TNFA, IL‐23A) were investigated in the three groups by RNASeq, RT‐qPCR, immunohistochemistry and immunofluorescence. RESULTS: Epidermal changes were already detectable in non‐lesional HS skin; the epidermal occurrence of antimicrobial peptides (AMPs), IL‐1β, TNF‐α and IL‐23 was highly upregulated compared with healthy AGR skin. In lesional HS epidermis, TNF‐α and IL‐1β expression remained at high levels while AMPs and IL‐23 increased even more compared with non‐lesional skin. In the dermis of non‐lesional HS skin, signs of inflammation were barely detectable (vs. AGR), while in the lesional dermis, the number of inflammatory cells and Th1/Th17‐related mediators were significantly elevated. CONCLUSIONS: Our findings that non‐lesional HS epidermal keratinocytes produce not only AMPs and IL‐1β but also high levels of TNF‐α and IL‐23 confirm the driver role of keratinocytes in HS pathogenesis and highlight the possible role of keratinocytes in the transformation of non‐inflammatory Th17 cells (of healthy AGR skin) into inflammatory cells (of HS) via the production of these mediators. The fact that epidermal TNF‐α and IL‐23 appear also in non‐lesional HS seems to prove these cytokines as excellent therapeutic targets

Sebum lipids influence macrophage polarization and activation

BACKGROUND: As lipids are known to regulate macrophage functions it is reasonable to suppose that a sebocyte - macrophage axis mediated by sebum lipids may exist. OBJECTIVE: To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids. METHODS: Oil-red-O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake FITC-Propionibacterium acnes were detected by FACS measurements. Cytokine protein levels were evaluated by ELISA and Western blot analysis. RESULTS: Sebaceous gland rich skin had an increased dermal lipid content compared to sebaceous gland poor skin to which all the tested sebum component lipids could contribute by penetrating through the dermo-epidermal barrier. Of the lipids, oleic and linoleic acids promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in Propionibacterium acnes activated macrophages, inhibiting the secretion of IL-1B, IL-6 and TNF-Alpha. Squalene, palmitic, stearic and oleic acids augmented the secretion of IL-1B even in the absence of Propionibacterium acnes, while oleic acid had a selective effect of inducing IL-1B, but down-regulating IL-6 and TNF-A secretion. CONCLUSIONS: Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathologic and therapeutic relevance. This article is protected by copyright. All rights reserved

Periodicities of paleoclimate variations in the first high-resolution non-orbitally tuned grain size record of the past 1 Ma from SW Hungary and regional, global correlations

This paper presents the results of grain-size analyses of an independently-dated loess/paleosol record dating back ca. 1 Ma from SW Hungary. The record follows an upward coarsening trend with a clear prevalence of coarse silts and fine sands. Variations are mainly controlled by fluctuations in sand input highlighting iterative changes in dust aerodynamics over the past 1 Ma in the source region found 50–100 km NW of our site. Based on our results regional factors influenced the intensity and nature of dust accumulation. Contrasting trends with the Chinese Loess Plateau in certain periods reflect a greater importance of the Atlantic region driving the evolution of nearby continental ice sheets. Proximity and expansion of these had significant impact on local wind field. Low topography of the surrounding mountain belts allowed for the intrusion of stronger cold winds, higher abrasion in the source region and transportation of coarser particles to the site from 700 to 450 ka. Another marked upward increase in grain-size from 400 ka can be linked to increasing continentality which along with tectonic activity resulted in a drop in the groundwater table in the source region and intensified erosion of formerly relatively stable surfaces bringing more coarse material to our site

New chronology of the best developed loess/paleosol sequence of Hungary capturing the past 1.1 ma:Implications for correlation and proposed pan-Eurasian stratigraphic schemes

In this paper, we are presenting a revised chronology of the best developed, longest (100 m) LPS in Hungary dating back 1.1 Ma: borehole Udvari-2A. It is based on a non-tuned age-depth model, built on the position of the Matuyama-Brunhes Boundary, Jaramillo and Olduvai Subchrons. Furthermore, on the assignment of formerly recorded uninterpreted geomagnetic reversals in both chrons. Other chronometric tools (AMS 14C dating, biostratigraphy, tephrostratigraphy) yielding absolute ages and/or ensuring validation of these were also used. Records of a Middle Pleistocene gastropod index fossil Neostyriaca corynodes (400 -140 ka) facilitated verification of ages between MIS 10 and MIS 6. Multiple age control points at 15, 25, 27, 45, 120, 191, 362, 430, 670, 780, 900, 990, 1070 ka were established for the last ca. 1.1 Ma. The resulting chronology is the best resolved independent one so far among Danubian Basin LPSs. In light of our data, the S3-S4 units were fused as S3 in all Serbian, and some Romanian sites and re-correlated with MIS 9. The results also point to a misassignment of the S5 units at these sites to MIS 13–15 leading to erroneous conclusions regarding paleoclimatic conditions and cyclicity. In our new stratigraphic scheme, these S5 paleosols were taken to represent the S4 paleosol and recorrelated with MIS 11. Finally, an ideal stratigraphic column dating back 1.1 Ma for SW Hungary was constructed and correlated with the Chinese loess/paleosol sequence of Xifeng and the benthic oxygen isotope record down to MIS 31