S100A9 Drives the Chronification of Psoriasiform Inflammation by Inducing IL-23/Type 3 Immunity.

Psoriasis is a chronic inflammatory skin disorder driven by the IL-23/type 3 immune response. However, molecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, which was confirmed in lesioned skin from patients with psoriasis and preclinical psoriasiform skin inflammation models. Genetic ablation or pharmacologic inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type 3 immunity in psoriasiform skin inflammation. In addition, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we showed an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type 3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis.

Screening for feature genes associated with hereditary hemochromatosis and functional analysis with DNA microarrays.

The aim of this study was to identify feature genes that are associated with hereditary hemochromatosis (HHC; iron overload) in cardiac and skeletal muscle of mice. First, the expression profile GSE9726 was downloaded from Gene Expression Omnibus database which included 12 samples. Then the differentially expressed genes (DEGs) were identified by R language. Furthermore, the KUPS software was used to identify relationships in interactions among common DEGs in the cardiac and skeletal muscles. We then used the EASE software to obtain enriched pathways in a gene interaction network. Finally, we used the plugins of the Cytoscape software, i.e., Mcode and Bingo, to conduct module analysis. By comparing diseased and normal tissue samples, 5 and 6 genes in the cardiac and skeletal muscles, respectively, were identified as DEGs. We observed that the S100a8 and S100a9 genes were common DEGs in both tissues examined. In addition, we constructed an interaction network with common DEGs and their interacting components, and identified S100a8 and S100a9 as being associated with immune responses. In view of the relationship between the early stage of myelodysplastic syndrome and the immune system, we hypothesize that the expression of the S100a8 and S100a9 genes is a feature that can be used for diagnosis during the early stage of the myelodysplastic syndrome and that the 2 genes could be used as targets in treating this disease.

Effect of the C-terminus of murine S100A9 protein on experimental nociception.

Calcium-binding protein S100A9 induces antinociception in mice evaluated by the writhing test. Similarly, a peptide identical to the C-terminus of murine S100A9 (mS100A9p) inhibits the hyperalgesia induced by jararhagin, a metalloprotease. Thus, we investigated the effect of mS100A9p on different models used to evaluate nociception. mS100A9p induced a dose-dependent inhibitory effect on the writhing test, and on mechanical hyperalgesia induced by carrageenan. mS100A9p inhibited thermal hyperalgesia induced by carrageenan. mS100A9p did not modify the nociceptive response in hot plate or tail-flick tests. These data demonstrate that the C-terminus of S100A9 protein interferes with control mechanisms of inflammatory pain.