Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common heritable peripheral neuropathy and results from a duplication on chromosome 17 that results in an extra copy and increased dosage of peripheral myelin protein 22 (PMP22). Zhao et al., in this issue of the JCI, successfully utilized antisense oligonucleotides (ASOs) to reduce PMP22 and ameliorated neuropathy in both mouse and rat models of CMT1A. These data confirm that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A and lay the groundwork for clinical trials in humans afflicted with this chronic, debilitating neurodegenerative disease.
Michael E. Shy
The inappropriate activation of transcription factors, including STATs, is known to promote tumor initiation and progression. The most common mechanisms of misregulation lead to constitutive activation of WT STATs. However, the recent discovery of rare STAT mutations in hematopoietic malignancies suggests that STAT mutants may be oncogenic. In this issue of the JCI, Pham et al. use a transgenic mouse model to demonstrate that STAT5BN642H is sufficient for the development of T cell neoplasia. This study, along with other studies of constitutively active STAT mutants, provides insight into the pathogenesis and treatment of STAT5-driven cancer.
Lisa N. Heppler, David A. Frank
Ubiquitylation is a tightly regulated process that is essential for appropriate cell survival and function, and the ubiquitin pathway has shown promise as a therapeutic target for several forms of cancer. In this issue of the JCI, Kedves and colleagues report the identification of a subset of gynecological cancers with repressed expression of the polyubiquitin gene UBB, which renders these cancer cells sensitive to further decreases in ubiquitin production by inhibition of the polyubiquitin gene UBC. Moreover, inducible depletion of UBC in mice harboring tumors with low UBB levels dramatically decreased tumor burden and prolonged survival. Together, the results of this study indicate that there is a synthetic lethal relationship between UBB and UBC that has potential to be exploited as a therapeutic strategy to fight these devastating cancers.
Diane L. Haakonsen, Michael Rape
The prevalence of food allergies has been increasing at an alarming rate over the last few decades. Despite the dramatic increase in disease prevalence, the development of effective therapies has not kept pace. In this issue of the JCI, Ando et al. provide a causal link between histamine-releasing factor (HRF) interactions with IgE and food allergy in a murine model. Successful oral immunotherapy of both egg-allergic human patients and food-allergic mice was associated with sustained suppression of HRF-reactive IgE levels. These results support a role for HRF-IgE interactions in the amplification of intestinal inflammation and suggest HRF as a therapeutic target in food allergy.
The NLRP3 inflammasome is a critical component of the innate immune system and can be activated in response to microbial and endogenous danger signals. Activation of the NLRP3 inflammasome results in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 result in a group of autoinflammatory diseases collectively known as the cryopyrin-associated periodic syndromes (CAPS). CAPS patients have traditionally been successfully treated with therapeutics targeting the IL-1 pathway; however, there are a number of identified CAPS patients who show only a partial response to IL-1 blockade. In this issue of the JCI, McGeough et al. demonstrated that TNF-α, in addition to IL-1β, plays an important role in promoting NLRP3 inflammasomopathies.
Balaji Banoth, Fayyaz S. Sutterwala
Mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the peripheral blood is a complex process that is enhanced dramatically under stress-induced conditions. A better understanding of how the mobilization process is regulated will likely facilitate the development of improved clinical protocols for stem cell harvesting and transplantation. In this issue of the JCI, Singh et al. (1) showed that the truncated cleaved form of neurotransmitter neuropeptide Y (NPY) actively promotes a breach of BM vascular sinusoidal portals, thereby augmenting HSPC trafficking to the circulation. The authors report a previously unrecognized axis, in which expression of the enzyme dipeptidylpeptidase-4 (DPP4)/CD26 by endothelial cells activates NPY-mediated signaling by increasing the bioavailability of the truncated form of NPY. These findings underscore the importance of and urgency to develop pharmacological therapies that target the vasculature and regulate diverse aspects of hematopoiesis, such as HSPC trafficking, in steady-state and stress-induced conditions.
Tomer Itkin, Jesús María Gómez-Salinero, Shahin Rafii
Cannabinoid receptor type-1 (CB1s) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide important insights into the regulation of adipocyte physiology by CB1. Mice with adipocyte-specific deletion of the CB1-encoding gene had an overall improved metabolic profile in addition to reduced body weight and total adiposity. These changes were associated with an increase in sympathetic tone of the adipose tissue and expansion of activated macrophages, both of which occurred prior to changes in body weight, lending support to a causal relationship between loss of CB1 in adipocytes and systemic metabolic changes. This work identifies adipocyte CB1s as a potential novel peripheral target for affecting systemic metabolism with diminished CNS effects.
Melody N. Hawkins, Tamas L. Horvath
The hematopoietic system declines with age, resulting in decreased hematopoietic stem cell (HSC) self-renewal capacity, myeloid skewing, and immune cell depletion. Aging of the hematopoietic system is associated with an increased incidence of myeloid malignancies and a decline in adaptive immunity. Therefore, strategies to rejuvenate the hematopoietic system have important clinical implications. In this issue of the JCI, Poulos and colleagues demonstrate that infusions of bone marrow (BM) endothelial cells (ECs) from young mice promoted HSC self-renewal and restored immune cell content in aged mice. Additionally, delivery of young BM ECs along with HSCs following total body irradiation improved HSC engraftment and enhanced survival. These results suggest an important role for BM endothelial cells (ECs) in regulating hematopoietic aging and support further research to identify the rejuvenating factors elaborated by BM ECs that restore HSC function and the immune repertoire in aged mice.
Vivian Y. Chang, Christina M. Termini, John P. Chute
Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER–associated degradation (ERAD) is responsible for the clearance of misfolded pro–arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus. The results of this study demonstrate a role for ERAD in neuroendocrine cells and serve as a clinical example of the effect of misfolded ER proteins retrotranslocated through the membrane into the cytosol, where they are polyubiquitinated, extracted from the ER membrane, and degraded by the proteasome. Moreover, proAVP misfolding in hereditary central diabetes insipidus likely shares common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of youth.
Daniel G. Bichet, Yoann Lussier
Glaucoma is a leading cause of blindness, with an estimated world-wide prevalence of 3.5% in members of the population older than 40 years of age. Elevated intraocular pressure as the result of abnormal resistance to aqueous humor drainage is a major contributing, and the only preventable, factor in glaucoma development. Schlemm’s canal (SC), a lymphatic-like vessel encircling the anterior portion of the eye, plays a key role in promoting aqueous humor outflow and maintenance of normal intraocular pressure. The risk of developing glaucoma increases with age; therefore, understanding mechanisms of SC maintenance and how aging affects SC function are of special importance, both for prevention and novel treatment approaches to glaucoma. Using a compelling array of genetic models, Kim et al. report in this issue of the JCI that continuous angiopoietin/TIE2 signaling is required for maintaining SC identity and integrity during adulthood and show that its age-related changes can be rescued by a TIE2 agonistic antibody.
Jeremiah Bernier-Latmani, Tatiana V. Petrova
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