In Brief

Innate immunity

Plexin-A4–semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm Wen, H. et al. J. Exp. Med. 22 Nov 2010 (doi:10.1084/jem.20101138)

This study shows that plexin A4 signalling synergizes with Toll-like receptor (TLR) signalling to promote pro-inflammatory cytokine responses. In the absence of plexin A4, macrophages showed defective production of interleukin-6 and tumour necrosis factor in response to various TLR agonists and bacteria. Activation of TLR signalling components was also defective in plexin A4-deficient macrophages. Physiological relevance for plexin A4-enhanced TLR responses was confirmed by the findings that plexin A4-deficient mice showed a reduced cytokine storm after lipopolysaccharide (LPS) treatment compared with wild-type mice and were protected from lethal challenge with LPS. Plexin A4-deficient mice were also resistant to septic inflammation induced by caecal ligation and puncture. Finally, administration of the plexin A4 ligand semaphorin 3A enhanced LPS-induced cytokine production, suggesting that this pathway could be a target in the treatment of sepsis.

Inflammation

Gene from a psoriasis susceptibility locus primes the skin for inflammation Wolf, R. et al. Sci. Transl. Med. 2, 61ra90 (2010)

The chronic skin inflammation of psoriasis could result from an abnormality of epidermal keratinocytes or from a dysregulated immune response. A combination of these factors is probably responsible for the disease, and a new study supports this idea by showing that S100 proteins expressed by keratinocytes activate an inflammatory cascade through the receptor for advanced glycation end products (RAGE). Transgenic mice overexpressing keratinocyte-restricted S100AA — the single mouse orthologue of the human proteins S100A7 and S100A15, which are encoded in psoriasis susceptibility locus 4 (PSORS4) and are highly expressed by keratinocytes from psoriatic lesions — had an exaggerated inflammatory response to wounding of the skin associated with increased levels of T helper 1 (T_H1) and T_H17 cell-associated cytokines. In turn, these cytokines further upregulated S100AA expression, showing the therapeutic potential of targeting the S100A7/A15–RAGE axis in psoriasis.

Mucosal immunology

T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract Engel, D. R. et al. Nature Med. 16, 1407–1413 (2010)

Localized intestinal surgery can disrupt the motility of the entire gastrointestinal tract (a condition termed postoperative ileus); this is thought to result from neuronal dysfunction. Using a mouse model, this study shows that it is not the nervous system but the immune system that drives postoperative ileus. Intestinal manipulation activated local dendritic cells to produce interleukin-12 and induce interferon-γ (IFNγ)-producing T helper 1 (T_H1) cells, which had dual roles in postoperative ileus: they drove the inflammation that disrupted the local environment and promoted the spread of intestinal dysfunction by migrating to other areas of the intestine. T_H1 cells that were induced in manipulated areas expressed the gut-homing receptor CC-chemokine receptor 9 (CCR9), which may have promoted their spread to other regions of the intestine. Interestingly, in patients undergoing abdominal surgery, the number of IFNγ-producing CCR9⁺ memory T cells in the blood was markedly increased shortly after the operation, but this population remained stable in patients undergoing non-abdominal surgery.