Articles in 2009

Inhibitors of α_vβ₃ and α_vβ₅ integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo. Such effects could compromise the anticancer efficacy of these agents in humans.

Signaling between endothelial and blood cell types controls inflammatory and thrombotic responses. Andrés Hidalgo and his coworkers now uncover a signaling mechanism by which the endothelium, acting on adherent leukocytes, promotes the capture of platelets or red blood cells by those leukocytes, contributing to pathology in mouse models of two very different types of disease—transfusion-related acute lung injury and sickle cell disease(pages 364–366).

New factors in wound healing are sorely needed. Here Youngsook Son and colleagues identify substance P, a small neuropeptide, as one such factor that seems to work by mobilizing stromal-like cells to the site of wounding, accelerating the healing process (pages 367–369).

Bali Pulendran and his colleagues explore ways that signaling through different pathogen receptors can program dendritic cells (DCs) to orchestrate inflammatory or tolerogenic immune responses. The yeast component zymosan triggers signaling through both Toll-like receptor 2 (TLR2) and the C-type lectin dectin-1. In the absence of TLR2, zymosan induces proinflammatory responses through dectin-1. But TLR2 triggering induces DCs to form the vitamin A–metabolizing enzyme Raldh2. The DCs can then form retinoic acid that acts in an autocrine manner on the DCs, programming them for the induction of regulatory T cell responses.

Bone is resorbed by osteoclasts, and too much activity by these cells leads to disease, such as osteoporosis. Here Kyoji Ikeda and colleagues show that the combined action of iron uptake and a key transcription factor involved in mitochondrial biogenesis are required for the proper functioning of these cells and that in cases of increased bone loss, iron chelation may be beneficial by inhibiting these cells.

During autophagy, cytosolic proteins and damaged organelles are delivered via autophagosomes to lysosomes, where they are degraded before presentation at the cell surface. Agents that induce autophagy have previously been shown to boost antigen presentation in vitro. Here Chinnaswamy Jagannath and colleagues show in mice that autophagy can be exploited to boost the efficacy of a dendritic cell vaccine for Mycobacterium tuberculosis.

Interleukin-10 is known to dampen immune responses and contribute to the persistence of chronic viruses and parasites. Thomas Braciale and his colleagues show in mice that the anti-inflammatory cytokine is produced, along with proinflammatory cytokines, by effector CD4⁺ and CD8⁺ T cells during an acute virus infection of the lung, thereby helping to regulate the extent of inflammatory lung damage in response to the virus.

The first phase 2 gene therapy trial for HIV-1 has shown some promising signs. There's a long way to go before this would be a viable approach in people with HIV—this trial did not show a statistically significant difference in viral load at the primary end point–but other analyses did reveal that the gene therapy seemed to have a modest, but statistically significant, effect at reducing viral load in the treated subjects versus the placebo arm. The study also provides some clues about what to improve in the future.

In this report, Skokowa et al. delineate a new molecular pathway by which synthesis of the metabolite NAD⁺ through the action of the enzyme NAMPT promotes myeloid cell differentiation. The potential clinical relevance of this pathway was demonstrated by showing that administration of vitamin B3, a precursor to NAD⁺, increases neutrophil counts in healthy individuals, and that defective myeloid cell differentiation in individuals with congenital neutropenia can be rescued in vitro by administration of NAMPT.

Inflammation plays a detrimental role in ischemic stroke. Now, Roland Veltkamp and his colleagues show that endogenous immunomodulatory T regulatory cells play a key part to dampen inflammation after stroke.

After injury to the spinal cord, hemorrhages occur both near and far from the initial lesion. J. Marc Simard and his colleagues demonstrate that spinal cord injury induces expression of the channel Trpm4 on endothelial cells in the spinal cord, which leads to their fragmentation and the spread of the hemorrhage.

Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain dilate and frequently hemorrhage. Benjamin Kleaveland et al. now provide evidence that CCM arises from defects in a signaling pathway involving the KRIT1 and CCM2 intracellular proteins (which have been previously implicated in CCM) and the HEG1 receptor; this pathway acts in endothelial cells and is required for vascular integrity. The role of the CCM2 protein in the endothelium is also explored in another paper published in this issue of Nature Medicine, by Kevin Whitehead et al.

Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain are prone to hemorrhage. Kevin Whitehead et al. now show that CCM2, mutations in which are associated with CCM, is needed for specific aspects of endothelial cell function involving RhoA GTPase. These defects can be partially restored by statin treatment, suggesting a potential therapeutic intervention for individuals with CCM. The role of CCM2 in the endothelium is also explored in another paper published in this issue of Nature Medicine, by Benjamin Kleaveland et al

A main function of fat cells is to store fuel for future use, which is released when the fat is broken down in a process called lipolysis. Here Hei Sook Sul and colleagues describe a new enzyme in fat, AdPLA, that inhibits lipolysis and shows that genetic deletion results in protection from obesity in two mouse models.

Identifying factors that influence response to cancer chemotherapy is crucial for improving its efficacy. Mauro Delorenzi and his colleagues report that a stromal gene expression signature predicts resistance to a commonly used chemotherapy regimen in individuals with estrogen receptor–negative breast tumors. These findings underline the potential of the tumor microenvironment to modulate tumor phenotype and the clinical response to treatment.