December 2015 | Volume 212, No. 13
Brief Definitive Reports
- Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy
Kelly et al. report the development of two highly selective and bioavailable small molecule IRAK4 inhibitors and show for the first time their therapeutic efficacy in autoimmune disorders and in a specific subset of diffuse large B cell lymphomas in mice.
- Melanocyte antigen triggers autoimmunity in human psoriasis
Arakawa et al. discovered that the autoimmune response in psoriasis is directed against melanocytes. They show that the main psoriasis risk allele HLA-C*06:02 mediates melanocyte-specific autoimmunity and identify ADAMTSL5 as a melanocyte autoantigen, which stimulates IL-17 and IFN-γ production in CD8+ T cells.
- The G protein–coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination
The orphan Gα13-coupled receptor P2RY8 promotes clustering of B cells at the follicle center in an FDC-dependent manner. Egress of Gα13 or Arhgef1 mutant GC B cells into circulation depends on the function of the promigratory receptor S1pr3.
- Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance
Vukovic et al. report that Hif-1α and Hif-2α are not required for leukemia stem cell maintenance and AML propagation, but they act synergistically to suppress leukemia development in mice. Furthermore, knockout of HIF-2α or pharmacological inhibition of the HIF pathway in human AML cells has no impact on their survival and proliferation under hypoxic conditions.
- IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
Koliaraki et al. report that IKKβ deletion in ColVI-expressing intestinal mesenchymal cells protects mice against inflammation-induced intestinal carcinogenesis. In contrast, a companion study by Pallangyo et al. shows that deletion of IKKβ by the Col1a2CreER promoter in intestinal fibroblasts leads to increased colitis-induced tumorigenesis. The two studies suggest that targeting IKKβ in different fibroblast populations by using different promoters might have opposite outcomes in intestinal cancer.
- IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis
Pallangyo et al. report that fibroblast-specific IKKβ deletion in Col1a2Cre-ERT2 mice promotes AOM/DSS-induced intestinal tumorigenesis, suggesting a tumor suppressor role for this kinase. In contrast, a companion study by Koliaraki et al. based on IKKβ deletion in ColVI-expressing intestinal mesenchymal cells suggests a role for IKKβ in promoting intestinal tumorigenesis. The two studies raise the awareness that in the context of tumorigenesis, IKKβ/NF-κB may have distinct functions in different fibroblast subpopulations.
- Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin
Inhibition of VE-PTP counters vascular leakage in inflammation via TIE-2, even in the absence of VE-cadherin.
- Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation
Phong et al. show that depending on the expression of p-Lyn, mast cell activation by antigen can result in dichotomous effects on mast cell function and signaling that can be accentuated by Tim-3 ligation.
- Insulin–InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages
Xia et al. report that insulin receptor signaling is required for lymphoid lineage specification in early lymphopoiesis via modulation of Ikaros expression. Disrupted insulin signaling generates more myeloid cells and fewer lymphoid cells, resulting in a skewed myeloid/lymphoid ratio in diabetic mice.