Brief Definitive Report
Yang et al. show that a disulfide isoform of HMGB1, with a role in TLR4 signaling, physically interacts with and binds MD-2. MD-2 deficiency in macrophage cell lines or in primary mouse macrophages stimulated with HMGB1 implicates MD-2 in TLR4 signaling. They also identify an HGMB1 peptide inhibitor, P5779, which when administered in vivo can protect mice from acetaminophen-induced hepatoxicity, ischemia/reperfusion injury, and sepsis.
Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity
Weber et al. report that neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. Their results identify a novel role for neutrophils in shaping the adaptive immune response.
Using a mouse model of multiple sclerosis (MS), the authors show that neutrophils expand in the bone marrow and accumulate in the circulation before clinical onset of disease. Early in disease development, neutrophils infiltrate the CNS, which is suppressed by G-CSF receptor deficiency and blockade of CXCL1 to ameliorate disease. In patients with MS, systemic expression of neutrophil-related mediators correlates with new lesion formation, lesion burden, and clinical disability.
Kulic et al. show that RBPJ, a transcriptional repressor of Notch, is frequently deleted in human cancers and can function as a tumor suppressor. Loss of RBPJ acts to derepress target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumor growth.
Burbage et al. use a mouse model of B-cell specific deficiency of Cdc42 to uncover an essential role of this Rho GTPase in B cells. They find that loss of Cdc42 results in aberrant B cell development, plasma cell differentiation, antigen presentation, and cellular interactions between B and T lymphocytes in vivo. All these defects led to notable functional defects in antiviral humoral immunity.
Chen et al. show that treatment with rapamycin, a drug known to inhibit mTOR signaling, rescues low bone density in mice with systemic sclerosis.
Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation
Using highly sensitive RNAseq to examine the whole transcriptome of enriched aortic hematopoietic stem cells and endothelial cells, the authors find G-protein–coupled receptor, Gpr56, is required to generate the first HSCs during endothelial to hematopoietic cell transition.
Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element
Majumder et al. explore the large-scale looping architecture of the Tcrb locus early in murine thymocyte development during the generation of TCRβ diversity. They dissect novel DNA regulatory elements controlling V to D-J recombination and identify within an insulator region a distally located CTCF-containing element functioning as a tether, which facilitates looping of distal Vβ to Dβ-Jβ regions and promotes locus contraction. A second CTCF-containing element, proximal to the Dβ-Jβ region, acts as a boundary, preventing the spread of active chromatin associated with Dβ-Jβ regions. Removal of the proximal boundary element impairs the locus contraction capabilities of the tethering element.