MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2

Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo. Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell–driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3′-UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down-regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis

Tectonic control on the distribution of onshore mud volcanoes in parts of the Upper Benue Trough, northeastern Nigeria

Onshore mud volcanoes are rare geological phenomena, which in Nigeria were reported for the first time few years ago in the Upper Benue Trough. In this study a detail geological mapping of the area of mud volcanoes occurrence was carried out, with the primary aim of defining their relationship, if any, to the structural geology there. The systematic field reconnaissance included field observations of the structural features, as well as analysis of the location and distribution of the onshore mud volcanoes, marking their locations on the topographic and geological maps, analysis of the aerial photographs and satellite images. The study area covered the central part of the Upper Benue Trough where the onshore mud volcanoes were found. The study area is the part of a sedimentary basin comprising Cretaceous clastic rocks that have been deformed intensively by a network of faults often embedded in the underlying Precambrian basement. This network of faults underwent a rejuvenation period from the Aptian to the Palaeocene. The most prominent tectonic structure in the study area is the NE - SW trending Kaltungo Fault Zone, however, there are other minor faults with N - S and NW - SE trends. This study shows that the mud volcanoes found in the study area are usually located near or within fault zones, within the outcropping Upper Cretaceous Yolde Formation and Upper Bima Sandstone, both of which were deformed by the Kaltungo faults, as well as by other minor faults. Worldwide, incidences of onshore mud volcano formation are usually attributed to areas of tectonic activity, rapid sedimentation or hydrocarbon occurrence. In this study, the interpretation of the field observations and mapping results, combined with information on the structural evolution of the study area and seismic pattern (very scarce), have led to the conclusion that the location of onshore mud volcanoes in the Upper Benue Trough, being located along the fault zones, is structurally controlled. The close relationship between mud volcano location and the structural framework of the area may be interpreted as one of several possible subsurface geological responses to present tectonic activity

Microbial community changes along the Ecology Glacier ablation zone (King George Island, Antarctica)

In recent years glacial surfaces have received much attention as microbial habitats of diverse photoautotrophic and heterotrophic cells. Supraglacial ecosystems are annually covered and uncovered by snow. The aim of this study was to investigate the microbial community response to changing environmental conditions in a transect following the receding snow line on the surface of Ecology Glacier (King George Island, Antarctica). Parameters of surface ice and cryoconite holes included chemical composition of ice and sediment, Bacteria diversity by denaturating gradient gel electrophoresis (DGGE), microbial functional diversity (Biolog Ecoplates), and microbial counts (epifluorescence microscopy, colony forming units - CFU). Data demonstrated profound differences between surface ice and cryoconite holes. Changing environmental factors along the transect influenced composition and abundance of the microbiocenosis in both habitat types. Several parameters correlated positively with distance from the glacier edge, including the cell morphotype Shannon Index, chlorophyll a, nitrogen and seston concentrations. Suspended solids content positively correlated with microbial 2 abundance and diversity. Nitrogen and phosphorus were limiting factors of microbial growth as amounts of organic nitrogen and phosphorus positively correlated with the cell numbers, fission rates and photoautotroph contribution. Our findings indicate that microbial community shows a response in terms of abundance and diversity to exposure of the glacial surface as snow-cover melts. To our knowledge this is the first study to recognize a microbial development pattern on a glacier surface in connection with the receding snow line. This may help better understand variability within supraglacial habitats, correct sampling procedures and inform biocenotic development models

Evidence of adaptation, niche separation and microevolution within the genus Polaromonas on Arctic and Antarctic glacial surfaces

Polaromonas is one of the most abundant genera found on glacier surfaces, yet it’s ecology remains poorly described. Investigations made to date point towards a uniform distribution of Polaromonas phylotypes across the globe. We compared 43 Polaromonas isolates obtained from surfaces of Arctic and Antarctic glaciers to address this issue. 16S rRNA gene sequences, intergenic transcribed spacers (ITS) and metabolic fingerprinting showed great differences between hemispheres but also between neighboring glaciers. Phylogenetic distance between Arctic and Antarctic isolates indicated separate species. The Arctic group clustered similarly, when constructing dendrograms based on 16S rRNA gene and ITS sequences, as well as metabolic traits. The Antarctic strains, although almost identical considering 16S rRNA genes, diverged into 2 groups based on the ITS sequences and metabolic traits, suggesting recent niche separation. Certain phenotypic traits pointed towardscell adaptation to specific conditions on a particular glacier, like varying pH levels. Collected data suggest, that seeding of glacial surfaces with Polaromonas cells transported by various means, is of greater efficiency on local than global scales. Selection mechanisms present of glacial surfaces reduce the deposited Polaromonas diversity, causing subsequent adaptation to prevailing environmental conditions. Furthermore, interactions with other supraglacial microbiota, like algae cells may drive postselectional niche separation and microevolution within the Polaromonas genus

Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis

OBJECTIVES: To integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis. METHODS: In this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed. RESULTS: We identified four SF clusters with respective marker genes: PRG4(+) SF (CD55, MMP3, PRG4, THY1(neg)); CXCL12(+) SF (CXCL12, CCL2, ADAMTS1, THY1(low)); POSTN(+) SF (POSTN, collagen genes, THY1); CXCL14(+) SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4(+) SF) and sublining (CXCL12(+) SF, POSTN(+) + and CXCL14(+) SF) SF subsets. CXCL12(+) SF and POSTN(+) + were most prominent in the fibroid while PRG4(+) SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4(+) SF correlated positively with disease severity parameters in the fibroid, POSTN(+) SF in the lymphoid pathotype whereas CXCL14(+) SF showed negative association with disease severity in all pathotypes. CONCLUSION: This study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

Acknowledgements We wish to thank Jorge Galán, Gregory Pazour, Derek Toomre, Giuliano Callaini, Joel Rosenbaum, Alessandra Boletta and Francesco Blasi for generously providing reagents and for productive discussions, and Sonia Grassini for technical assistance. The work was carried out with the financial support of Telethon (GGP11021) and AIRC.Peer reviewedPostprin

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation