ON THE COVER
Rodriguez-Laguna et al. show that somatic mutations in PIK3CA can cause generalized lymphatic anomaly in humans. The cover shows the hyperplastic lymphatic network in a mouse model that expresses one of the mutations identified in humans (Pik3ca H1074R), specifically within their lymphatic endothelial cells. The image was taken from the original manuscript and modified by the JEM editorial office. See page 407.
- PDF Icon PDF LinkTable of Contents
Found in Translation
Carballido and Santamaria discuss the opportunities and challenges of moving preclinical antigen-specific approaches into the clinic.
In this review, Zheng and Cantley provide a historical perspective of the folate metabolism field, delve into folate chemistry that is often overlooked, and point out various missing links and underdeveloped areas in folate metabolism for future exploration.
Brief Definitive Reports
This study shows that mice with an ALS-linked heterozygous Tbk1 deletion are normal until at least 200 d of age. However, proteostatic and neuroinflammatory challenge by additional expression of mutant SOD1 unmasks a two-edged role of TBK1 in motoneuron disease.
3K3A-APC exerts beneficial therapeutic effects in models of neurological disorders and is currently in development for human stroke. The authors show that 3K3A-APC inhibits BACE1 amyloidogenic pathway in mice, suggesting 3K3A-APC is an effective antiamyloid prevention therapy for Alzheimer’s disease.
SARM1 is the central executioner of the axonal degeneration program. Here, Geisler et al. developed SARM1 dominant-negative transgenes that potently block pathological axon degeneration in vitro and in vivo by inhibiting wild-type SARM1, an approach that could be translated to the clinic.
Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies
Kosik et al. report that antibodies binding to influenza A virus hemagglutinin stem exert antiviral activity by inhibiting viral neuraminidase, inhibiting nascent virion release from infected cells, and enhancing Fc-triggered activation of innate immune cells.
T follicular helper cells promote the generation of protective antibodies, but can also foster pathogenic antibodies. The ATP-gated P2X7 receptor selectively limits the expansion of Tfh cells that amplify self-reactive antibodies in systemic lupus erythematosus.
Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10
Appropriate macrophage responsiveness to IL-10 is crucial for the maintenance of gut immune homeostasis. Xiao et al. demonstrate that phosphatase Shp2 restrains IL-10–mediated deactivation of macrophages and thus supports the progression of intestinal inflammation.
Neutrophil extracellular traps (NETs) can maintain chronic inflammation. Weckbach et al. provide evidence that neutrophil infiltration and NET formation driven by the cytokine midkine foster cardiac inflammation in myocarditis.
Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
In autoimmune myocarditis, self-reactive T cells attack cardiac antigens and contribute to heart inflammation. In this study, Anzai et al. show that the T cell–derived cytokine and growth factor IL-3 amplifies inflammation and exacerbates autoimmune myocarditis.
A functional genomics approach uncovers previously undescribed cell type–dependent responses that can be linked to the immunoregulatory actions of glucocorticoids in humans.
Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). Here, Rodriguez-Laguna et al. report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of GLA.
Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer
Head and neck cancer patients taking NSAIDs with PIK3CA tumor alterations demonstrate improved survival. Studies in relevant preclinical models implicate signaling via COX2-mediated production of PGE2 as an underlying mechanism for this survival benefit.
Wnt5a from osteoblastic niche induces and maintains the dormancy of prostate cancer cells in bone and inhibits bone metastasis in a preventive manner, uncovering a potential therapeutic utility of Wnt5a in the treatment of bone metastatic prostate cancer.
This study identifies a novel therapeutic strategy against cisplatin-resistant lung squamous cell carcinoma (LSCC) using mouse models and patient samples. LSCC chemoresistance depends on LUBAC and high NF-κB activity, mechanisms that can be targeted to increase therapy response.