Immune tolerance to allogenic transplanted tissues remains elusive, and therapeutics promoting CD4+FOXP3+ Tregs are required to achieve this ultimate goal. In this issue of the JCI, Efe and colleagues engineered an Fc domain fused to a human mutein IL-2 (mIL-2–Fc) bearing mutations that confer preferential binding to the high-affinity IL-2 receptor expressed on Tregs. In vivo mIL-2–Fc therapy effectively heightened mouse, monkey, and human Treg numbers, promoted tolerance to minor antigen mismatched skin grafts in mice, and synergized with immunosuppressive drugs used in the clinic. These findings warrant clinical trials that assess the efficacy of mIL-2–Fc in transplantation.
Geoffrey Camirand, Fadi G. Lakkis
The physiology of lipid droplets (LDs) has been most extensively characterized in adipocytes, but LDs also accumulate in endothelial cells lining blood vessels in response to changing levels of triglycerides. In recent issues of the JCI, two independent papers highlight a direct role of endothelial LDs in the genesis of hypertension and atherosclerosis in rodent models. Kim et al. demonstrated that accumulation of LDs in the endothelium leads to hypertension, impairs endothelial function, and accelerates atherosclerosis. Boutagy, Gamez-Mendez, et al. knocked out Atgl in the endothelium and confirmed triglyceride accumulation in endothelial cells that was associated with reduced NO synthesis and impaired endothelial-dependent vasodilation. These data suggest that enhancing triglyceride breakdown in the endothelium could provide a treatment target for patients with metabolic syndrome.
Iris Z. Jaffe, S. Ananth Karumanchi
The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer’s disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.
Aleksanteri Aspelund, Kari Alitalo
NKT cells recognize glycolipids presented by CD1d-expressing antigen-presenting cells (APCs) and include type I NKT cells with antitumor function and type II NKT cells, which have been reported to suppress the antitumor response. Some type II NKT cells recognize sulfatide, a glycosphingolipid with a sulfate modification of the sugar. Type I NKT cells recognize different glycosphingolipids. In this issue of the JCI, Nishio and colleagues showed that APCs could process sulfatide antigens, analogous to protein processing for peptide-reactive T cells. Antigen processing in lysosomes removed sulfate to generate a glycosphingolipid that stimulated type I NKT cells and thereby turned an antigen with no antitumor activity into one that not only stimulated type I NKT cells but also stimulated antitumor responses. These findings may extend to the development of glycolipid antigens that could stimulate anticancer responses via antigen processing by APCs.
Mitchell Kronenberg, Isaac Engel
Chronic low-grade inflammation is increasingly recognized as a subtle yet potent risk factor for a multitude of age-related disorders, including respiratory diseases, cardiovascular conditions, metabolic syndromes, autoimmunity, and cancer. In this issue of the JCI, Mebratu, Jones, and colleagues shed new light on the mechanisms that promote low-grade airway inflammation and how this contributes to the development of chronic obstructive pulmonary disease (COPD). Their finding that Bik deficiency leads to spontaneous emphysema in female mice, but not in males, marks a notable advancement in our understanding of how inflammatory processes can diverge based on biological sex. This finding is of clinical relevance, given the vulnerability of women to developing COPD.
Irina Petrache, David W.H. Riches
Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.
Haikuo Li, Benjamin D. Humphreys
Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor–associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIF1A-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors.
Yadong Xie, Haohao Zhang, Xinyang Song
Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recapitulated BII symptoms and increased Th1 cell populations. Notably, macrophages in the periprosthetic tissue from BII patients were more likely to exhibit a proinflammatory phenotype, and naive T cells exposed to 10-HOME caused naive macrophages to differentiate to a proinflammatory phenotype. This work provides a pathophysiologic mechanism for a currently understudied and poorly characterized disease.
Tyler M. Bauer, Katherine A. Gallagher
A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel–based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, as a means of regulating the cellular response to oxidative stress. CTH-mediated conversion of cystathionine to cysteine was necessary for regulating reactive oxygen species to support invasion. Meanwhile, inhibition of CTH suppressed the invasive glioblastoma phenotype. However, inhibiting CTH resulted in a larger overall tumor mass. These findings suggest that targeting the transsulfuration pathway may serve as a means of redirecting glioblastoma to proliferate or invade.
András K. Ponti, Daniel J. Silver, Christopher Hine, Justin D. Lathia
Dengue fever, caused by four distinct serotypes of the dengue virus (DENV1–4), poses a public health concern for much of the world. The NIH’s Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) has developed a series of single-dose, live-attenuated tetravalent DENV vaccines, including TV005. However, phase III trials require a lengthy three-to-five year follow-up. In contrast, controlled human infection models (CHIMs) offer a faster means to assess vaccine efficacy for any of the four serotypes. In this issue of the JCI, Pierce, Durbin, and colleagues conducted a CHIM study with attenuated DENV2 and DENV3 challenge viruses in individuals six months after vaccination with TV005. The TV005 vaccine was well tolerated and effectively protected all vaccinated individuals from viremia and rash during challenges with DENV2 or DENV3. Notably, vaccine recipients also showed serotype-specific efficacy. While long-term studies are still needed, these findings represent an important step in providing protection against dengue virus.
Annelies Wilder-Smith
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