Issues

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.

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.

Autosomal-recessive IL-17RA, IL-17RC, and ACT1 deficiencies and autosomal-dominant IL-17F deficiency in humans underlie susceptibility to chronic mucocutaneous candidiasis.

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.

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.

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.

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.

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.

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.

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.

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.

Osteocalcin (Ocn)-expressing bone marrow cells produce the Notch ligand DLL4, and this is required for lymphoid progenitor cells to seed the thymus.

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 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.

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.