May 2015 | Volume 212, No. 5
- Precision medicine: Clarity for the clinical and biological complexity of Alzheimer’s and Parkinson’s diseases
Alzheimer’s and Parkinson’s diseases, two of the most common neurodegenerative diseases, could benefit from optimally targeted and timed interventions tailored to individual patient disease. The topic is discussed in a perspective on precision medicine by Montine and Montine.
Brief Definitive Report
- SIRT1 deacetylates RORγt and enhances Th17 cell generation
Lim et al. demonstrate that protein deacetylase, Sirtuin 1, promotes autoimmunity by deacetylating RORγt increasing its transcriptional activity and promoting Th17 differentiation and function. Blockade or loss of Sirtuin 1 results in protection from multiple sclerosis-like disease in mice.
- Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis
Autosomal-recessive IL-17RA, IL-17RC, and ACT1 deficiencies and autosomal-dominant IL-17F deficiency in humans underlie susceptibility to chronic mucocutaneous candidiasis.
- Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence
Kim et al. identify a novel shear stress–induced pathway involving protein kinase A, CREB, and bone morphogenetic protein that regulates hematopoietic stem cell generation in the embryonic aorta.
- Adenosine signaling promotes hematopoietic stem and progenitor cell emergence
Jing and colleagues show that adenosine signaling plays an important evolutionary role in the first step of hematopoietic stem cell generation in the embryonic aorta.
- Biomechanical forces promote blood development through prostaglandin E2 and the cAMP–PKA signaling axis
Diaz et al. show that biochemical forces induced by blood flow promote the development of hematopoietic cells at early embryonic stages via induction of prostaglandin E2 and signaling pathways involved in hematopoiesis.
- TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
Wu et al. use a mouse model to show that active respiratory viral infection triggers TREM-2 expression on the macrophage cell surface and thereby prevents macrophage apoptosis during the acute illness. In addition, long after viral clearance, IL-13 and DAP12 promote TREM-2 cleavage to its soluble form that unexpectedly also enhances macrophage survival and promotes chronic inflammatory disease.
- Alveolar macrophage–derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes
Goritzka et al. describe a role for recruited inflammatory monocytes in antiviral immunity and protection from RSV infection in mice. The authors demonstrate that this is critically dependent on the production of type I IFNs by alveolar macrophages triggered via RIG-I–like receptors, thus highlighting an important cell-extrinsic mechanism of type I IFN–mediated antiviral activity.
- ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis
Protective CD4 T cells specific for M. tuberculosis (Mtb) are maintained in the lungs during active Mtb infection. Similar to memory CD4 T cells, persistence of these Mtb-specific cells requires intrinsic expression of Bcl6 and ICOS.
- Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling
SOCS1 and -3 proteins are released by alveolar macrophages into exosomes and microparticles, respectively, which are then taken up by alveolar epithelial cells, resulting in inhibition of STAT signaling. This process was dampened by exposure to cigarette smoke and may thus be important in suppressing airway inflammation.
- Modular expression analysis reveals functional conservation between human Langerhans cells and mouse cross-priming dendritic cells
In depth phenotyping and functional analysis of skin dendritic cell subsets suggests that the function of Langerhans cells may not be conserved between mouse and human and supports the idea that human Langernhans cells may be a relevant therapeutic target.
- Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow
Osteocalcin (Ocn)-expressing bone marrow cells produce the Notch ligand DLL4, and this is required for lymphoid progenitor cells to seed the thymus.
- DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma
Using DNA methylation and gene expression profiling of diffuse large B cell lymphoma (DLBCL) samples, Schmid et al. find that the dual-specificity phosphatase DUSP4 gene is highly methylated in nodal and extranodal DLBCL cases, which correlates with loss of DUSP4 expression. Low DUSP4 expression represents a negative prognostic factor in patient cohorts. Ectopic DUSP4 expression inhibits JNK signaling and induces apoptosis in DLBCL cells. This effect can be phenocopied by JNK inhibitors in vitro and in vivo.
- The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation
The transcription factor LEF1 promotes the expansion and Th2-type polarization of invariant NKT cells in part by directly inducing the expression of the IL-7 receptor component CD127 and the transcription factors c-myc and Gata3.
- An anti-silencer– and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development
Hao et al. report that a distant anti-silencer element interacts with the Rag1 and Rag2 gene promoters in double-positive thymocytes and that SATB1 is a regulator of Rag locus organization in these cells.