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
Chromatin modification influences gene expression by either repressing or activating genes, depending on the specific histone mark. Chromatin structure can also influence alternative splicing of transcripts; however, the mechanisms by which epigenetic marks influence splicing are poorly understood. A report in the current issue of the JCI highlights the biological importance of the coordinated control of alternative pre-mRNA splicing by chromatin structure and transcriptional elongation. Yuan et al. found that mutation of the histone methyl transferase SEDT2 affects alternative splicing fates of several key regulatory genes, including those involved in Wnt signaling. As a consequence, loss of SEDT2 in the intestine aggravated Wnt/β-catenin signaling effects, thereby leading to colorectal cancer.
Alberto R. Kornblihtt
Transplantation of human neural stem cells has long been proposed as a potential strategy for treating CNS injury and disease; however, application of this approach has had limited therapeutic benefit. Yet compared with rodents and other experimental mammals, humans have a relatively long time window for development of the brain and spinal cord. In this issue of the JCI, Lu and colleagues asked whether the results of neural stem cell transplantation might be improved by accommodating the protracted development of human neural cells. They used a rodent model of spinal cord injury, in which human neural progenitor cells were transplanted at the site of damage. While there was no observable benefit at early time points after transplantation, both anatomic and functional improvements in the injured animals emerged over the course of a year. In particular, the human progenitor cell population differentiated, matured, and integrated into the rodent spinal cords over a time frame that aligned with the normal development of these cells in humans. This study demonstrates that neural stem cells may offer significant therapeutic benefit after CNS injury; however, this process may take time and demands patience on the part of investigators, patients, and clinicians alike.
Steven A. Goldman
Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease.
Lewis J. Smith
The blood brain barrier (BBB) and the glia limitans serve to prevent the migration of cells and other large molecules from the blood into the CNS. Neuroinflammatory diseases are characterized by disruption of the BBB and increased leukocyte infiltration into the CNS. In this issue of the JCI, Horng and colleagues demonstrate that astrocytes of the glia limitans induce tight junction formation in response to inflammatory cues, thereby tightening the border to limit the number of activated T cells infiltrating the CNS. Moreover, preventing the formation of this inducible barrier in mice increased disease severity in models of neuroinflammation. Together, the results of this study indicate that the inducible barrier of the glia limitans should be further explored as a therapeutic target.
Francisco J. Quintana
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