Summary Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent but not commensal S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMα induces the release of keratinocyte IL-1α and IL-36α, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1α and IL-36α, as well as IL-17 production by γδ T cells and ILC3 and neutrophil infiltration to the site of infection were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a−/−f−/− mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMα drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection.

for both prokaryotic and eukaryotic enzymes is largely conserved. However there are several structural differences between prokaryotic UGM and eukaryotic AfUGM mainly because of five additional inserts in AfUGM, two of with play an important role in tetramerization. Comparing the un-complexed, native AfUGM structure and the ligandbound AfUGM structure (both oxidized and reduced FAD) allowed us to address structural changes (loop movements) that play an important role in substrate binding and redox state. Structural binding studies on AfUGM revealed a unique substrate binding mechanism significantly different from proUGMs. This has helped us in identifying important conserved residues in AfUGM substrate binding and recognition. Based on the crystal structure we have made mutants of important active site residues.

Focal areas of hyperpermeability in CSC may be derived from the leakage of tiny punctate spots in the inner choroid. Hyperpermeability of these lesions may be involved in the development of serous retinal detachment associated with CSC.

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Neuroinflammation involving CC chemokines such as monocyte chemoattractant protein-1 (MCP-1) has been demonstrated in the pathological process of retinitis pigmentosa (RP), an inherited degenerative retinal disease. However, the mechanism of MCP-1 and its receptor CCR2 involvement in the disease remains unclear. To investigate the role of MCP1/CCR2 in RP pathogenesis, ccr2 mutant RP mice (ccr2(-/-) rd10) were created and analyzed. The expression of MCP-1, RANTES, stromal cell-derived factor (SDF-1), and tumor necrosis factor-α (TNF-α) in the retinas of wild-type, rd10, and ccr2(-/-) rd10 mice was analyzed using quantitative RT-PCR. Photoreceptor apoptosis (TUNEL staining) and the number of microglia (positive for the F4/80 antibody) in the retina were examined. Retinal function was assessed using electroretinograms, and the structure of the whole retina was analyzed from images obtained using optical coherence tomography (OCT) and by histological examination. The expression levels of MCP-1, RANTES, and SDF-1 increased with time in the rd10 mice but not in the wild-type mice. Rearing the mice in the dark prevented degeneration and resulted in thicker photoreceptor layers at each time point. In those mice, the peaks of chemokine expression shifted to a later time with degeneration, suggesting that the expression of these chemokines was induced during the progression of degeneration. Although the difference was not so obvious, the retina in the ccr2(-/-) rd10 mice was consistently and significantly thicker than that in the rd10 (ccr2(+/+) rd10) mice at all time points. Rhodopsin gene expression was also higher in the ccr2(-/-) rd10 mice than in rd10 (ccr2(+/+) rd10) mice, suggesting photoreceptor survival in the former. Retinal function was also better preserved in the ccr2(-/-) rd10 mice than in the rd10 mice. The number of microglia in the retinas of the ccr2(-/-) rd10 mice was significantly lower than that in the retinas of the rd10 mice. Interestingly, the MCP-1 induction that was observed in the retinas of the rd10 mice was diminished in the retinas of the ccr2(-/-) rd10 mice. Our results suggest that the MCP-1/CCR2 system plays a role in retinal degeneration in rd mouse retinas. Retinal MCP-1 expression in the rd mouse retina may be partially controlled by ccr2-positive circulating cells.