Commentary
Abstract
Invasive fungal infections carry high morbidity and mortality, but there are no fungal vaccines. In this issue of the JCI, Okaa et al. report that endonuclease 2 (Eng2), an antigen shared by the Blastomyces, Histoplasma, and Coccidioides species of fungi, elicits protective immunity in mice against blastomycosis, histoplasmosis, and coccidioidomycosis. These results establish a common antigen that can elicit protection against multiple mycoses, encouraging the development of a pan-fungal vaccine. The road to fungal vaccines is made difficult by the need for effectiveness in immunocompromised individuals, the sporadic nature of fungal disease, and the economics of vaccine development. Despite these hurdles, there is optimism that such vaccines can be developed and perhaps find usefulness as adjuncts to antifungal therapy.
Authors
Arturo Casadevall
Abstract
DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers — Fassihi et al. and Nakazawa et al. — describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies’ characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.
Authors
Arjan F. Theil, Jan H.J. Hoeijmakers
Abstract
Glycogen synthase kinase-3β (GSK3β) is an established regulator in the DNA double-strand break (DSB) repair pathway. Recent work by Allam et al. revealed a mechanism of DSB repair pathway choice through GSK3β-mediated, site-specific phosphorylation of the tumor suppressor p53 binding protein 1 (53BP1) at threonine 334 (T334). 53BP1 T334 phosphorylation prevented interaction between 53BP1 and its downstream functional partners, PTIP and RIF1, thereby inhibiting 53BP1-directed nonhomologous end joining (NHEJ). Additionally, 53BP1 T334 phosphorylation promoted recruitment of CtIP and RPA32 to DNA damage sites to facilitate homologous recombination (HR). In contrast with loss of 53BP1 function, a 53BP1 T334A phospho-deficient mutant accumulated aberrantly at DSBs, where it impaired end resection and suppressed HR activity. These surprising results suggest that GSK3β may select between NHEJ and HR DNA repair pathways. Additionally, these data support targeting the GSK3β/53BP1 axis to enhance PARP inhibitor efficacy in solid tumors, regardless of BRCA1 status.
Authors
Justin W. Leung, David Gius
Abstract
Pulmonary fibrosis, an unrelenting disease of lung scarring, has been associated with the expansion of a profibrotic fibroblast population and extensive extracellular matrix deposition. In this issue, Molina and colleagues provide foundational mechanistic evidence that fibroblast proliferation itself is a critical driver of fibrosis. Using lineage tracing in preclinical fibrosis models, the authors showed that naive Scube2+ alveolar fibroblasts underwent a profibrotic phenotypic switch prior to proliferating within areas of fibrotic remodeling. Induction of apoptosis via Esco2 deletion or directly preventing proliferation via Ect2 deletion in these fibroblasts attenuated fibrosis. Complementary analyses on explanted human lung tissue confirmed translational relevance, collectively providing compelling evidence for the importance of fibroblast proliferation in fibrotic disease.
Authors
Cody A. Schott, Elizabeth F. Redente
Abstract
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset inflammatory disorder caused by somatic UBA1 mutations in hematopoietic stem cells. UBA1 encodes a key enzyme that catalyzes protein ubiquitination. Clinically, VEXAS is characterized by systemic inflammation and hematologic abnormalities. Patient studies have hinted that the transition of UBA1-mutated stem cells into proinflammatory myeloid precursors may propagate the manifestations of VEXAS syndrome. In this issue of the JCI, Dong and colleagues developed nine unique conditional knockout mouse strains and found that only neutrophil-specific Uba1 deletion reproduced VEXAS syndrome–like findings. The observed phenotype was at least in part due to inflammatory reprogramming and longer survival of the mutant neutrophils. In addition to deepening our mechanistic understanding of VEXAS syndrome pathogenesis, this work should provide a platform to pursue more targeted approaches to treatment.
Authors
Ajay Tambralli, Jason S. Knight
Abstract
In systemic lupus erythematosus (SLE), autoimmunity often develops toward self nucleic acids. The nucleic acid receptors TLR7 and TLR9, which sense RNA and DNA, respectively, are critical for the generation of pathogenic autoimmune antibodies. Despite similarities in their downstream signaling cascades, these receptors play opposing roles in most mouse lupus models: TLR7 promotes disease, while TLR9 provides protection — an observation often referred to as “the TLR paradox.” To understand the basis of this dichotomy, Leibler et al. created genetically edited lupus-prone mice in which TLR7 receptors express the TLR intracellular signaling domain (TIR) that corresponds to TLR9, or vice versa. Their results revealed that the TIR domains contribute to the receptors’ opposing roles in SLE, shedding light into the TLR paradox in autoimmunity.
Authors
Roser Tachó-Piñot, Carola G. Vinuesa
Abstract
Osteoarthritis (OA) is a highly prevalent and painful joint disease in desperate need of disease-modifying therapeutics. Decline in the activity of the Forkhead box O (FOXO) family of transcriptional regulators in articular chondrocytes may contribute to the development of OA. In a study in this issue of the JCI, Kurakazu et al. screened compounds for FOXO activators and discovered that the antihistamine cyproheptadine activated FOXO3 through inhibition of the histamine H1 receptor. Cyproheptadine modulated the activity of OA-relevant pathways and reduced the severity of joint damage and pain behavior in a mouse model of OA, thus showing potential for development as a disease-modifying OA drug.
Authors
Richard F. Loeser, Philip R. Coryell
Abstract
Increased activation of the NLRP3 inflammasome in immune cells, including macrophages, has been implicated in the pathogenesis of multiple chronic inflammatory diseases. Targeted depletion of macrophages has been explored as a cross-disease therapeutic strategy, but without subtype-specific markers, this strategy risks elimination of macrophages with homeostatic functions. In this study, Liu et al. identified a subpopulation of pathogenic macrophages, referred to as Toe-Macs, which are characterized by overexpression of the DNA demethylase TET3 in metabolic dysfunction–associated steatohepatitis (MASH), non–small cell lung cancer (NSCLC), and endometriosis. When induced into the disease microenvironment, Toe-Macs produced proinflammatory cytokines and chemokines. Selective elimination of Toe-Macs attenuated disease progression without any discernible side effects in mouse models of MASH and NSCLC. These findings highlight the role of Toe-Macs in the pathogenesis of chronic inflammatory diseases and provide a rationale for exploring TET3 as a therapeutic target.
Authors
Shojiro Haji, Yoshihiro Ogawa
Abstract
In acute myeloid leukemia (AML), leukemogenesis is typically driven by the sequential acquisition of distinct classes of mutations that collaborate to transform normal hematopoietic stem and progenitor cells. The founding and cooperating mutations in AML are often in signaling genes and form functional partnerships with each other, each addressing complementary aspects of malignant transformation. In this issue of the JCI, Kramer et al. elaborate on the molecular pathogenesis of AML. By using a mouse bone marrow model bearing the common AML-initiating mutations in DNA methyltransferase 3 α (DNMT3A) and nucleophosmin 1 (NPM1), the work provides further evidence for the role of the signaling orchestrator GRB2-associated–binding protein 2 (GAB2) in AML progression, positioning GAB2 as a potential therapeutic target.
Authors
Amanda Luvisotto, Lu Wang
Abstract
Celiac disease, an enteropathy driven by a maladaptive immune response to dietary gluten, is marked by increased proliferation in intestinal crypts, or crypt hyperplasia. However, it is unknown whether this phenomenon is a compensatory response to loss of villus epithelial cells or if it is driven by independent mechanisms. In this issue of the JCI, Stamnaes et al. demonstrated that in untreated celiac disease, crypt cells had increased expression of proteins involved in the IFN response, with decreased expression of fatty acid metabolism pathways. These expression patterns were recapitulated in mice treated with IFN-γ, but not mice with intestinal epithelial cell–specific knockout of the IFN-γ receptor. The findings suggest that crypt cells were reprogrammed directly by IFN-γ signaling, independent of changes to epithelial villi.
Authors
Alexa R. Weingarden
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