T-cell contact-dependent regulation of CC and CXC chemokine production in monocytes through differential involvement of NFκB: implications for rheumatoid arthritis

We and others have reported that rheumatoid arthritis (RA) synovial T cells can activate human monocytes/macrophages in a contact-dependent manner to induce the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNFα). In the present study we demonstrate that RA synovial T cells without further activation can also induce monocyte CC and CXC chemokine production in a contact-dependent manner. The transcription factor NFκB is differentially involved in this process as CXC chemokines but not CC chemokines are inhibited after overexpression of IκBα, the natural inhibitor of NFκB. This effector function of RA synovial T cells is also shared by T cells activated with a cytokine cocktail containing IL-2, IL-6 and TNFα, but not T cells activated by anti-CD3 cross-linking that mimics TCR engagement. This study demonstrates for the first time that RA synovial T cells as well as cytokine-activated T cells are able to induce monocyte chemokine production in a contact-dependent manner and through NFκB-dependent and NFκB-independent mechanisms, in a process influenced by the phosphatidyl-inositol-3-kinase pathway. Moreover, this study provides further evidence that cytokine-activated T cells share aspects of their effector function with RA synovial T cells and that their targeting in the clinic has therapeutic potential

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Mass spectrometric metabolomic imaging of biofilms on corroding steel surfaces using laser ablation and solvent capture by aspiration

Ambient laser ablation and solvent capture by aspiration (LASCA) mass spectrometric imaging was combined with metabolomics high-performance liquid chromatography (HPLC) mass spectrometry analysis and light profilometry to investigate the correlation between chemical composition of marine bacterial biofilms on surfaces of 1018 carbon steel and corrosion damage of steel underneath the biofilms. Pure cultures of Marinobacter sp. or a wild population of bacteria present in coastal seawater served as sources of biofilms. Profilometry data of biofilm-free surfaces demonstrated heterogeneous distributions of corrosion damage. LASCA data were correlated with areas on the coupons varying in the level of corrosion attack, to reveal differences in chemical composition within biofilm regions associated with corroding and corrosion-free zones. Putative identification of selected compounds was carried out based on HPLC results and subsequent database searches. This is the first report of successful ambient chemical and metabolomic imaging of marine biofilms on corroding metallic materials. The metabolic analysis of such biofilms is challenging due to the presence in the biofilm of large amounts of corrosion products. However, by using the LASCA imaging interface, images of more than 1000 ions (potential metabolites) are generated, revealing striking heterogeneities within the biofilm. In the two model systems studied here, it is found that some of the patterns observed in selected ion images closely correlate with the occurrence and extent of corrosion in the carbon steel substrate as revealed by profilometry, while others do not. This approach toward the study of microbially influenced corrosion (MIC) holds great promise for approaching a fundamental understanding of the mechanisms involved in MIC. (C) 2015 American Vacuum Society