Issues
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MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer
Bhin et al. show that MYC activation drives resistance to mTOR inhibitors and is significantly associated with poor response to mTOR inhibition in breast cancer patients, suggesting the potential of MYC as a biomarker for predicting resistance to mTOR-targeted therapies.
Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH
Lysosomal cholesterol overload triggers phenotypic changes and profibrotic activation of macrophages around dead hepatocytes containing cholesterol crystals in the development of NASH. Cholesterol excretion from macrophages using β-cyclodextrin polyrotaxane, which is designed to release β-cyclodextrin in lysosomes, alleviates liver fibrosis.
Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis
Chakraborty et al. demonstrate that a subset of tissue-resident alveolar macrophages shows greater capacity for efferocytosis and prevents hyperinflammation following repeated pathogen challenges. These trained alveolar macrophages exhibit upregulation of the efferocytosis receptor MERTK mediated by the transcription factor KLF4.
The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling
Sandner et al. uncover a key role for the guanine nucleotide exchange factor Rinl in restraining Tfh differentiation via CD28 signaling in homeostasis, immunization models, virus infection, and aging in mice, and in cultures of human CD4+ T cells.
A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
Neuroinflammation is a feature of many neurodegenerative diseases, including Alzheimer's disease. We discovered a new class of molecules with promising potential for clinical application that reduce hallmarks of neuroinflammation by inhibiting the PU.1 transcription factor, a master regulator of inflammation.
Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
Aoun et al. demonstrate that autoreactive B cells, which target collagen type II protein, are present in the natural B cell repertoire of various species. These B cells play a crucial role in tolerizing T cells and suppressing tissue-specific autoimmune inflammation.
IL-6 translation is a therapeutic target of human cytokine release syndrome
This study repurposes metoprolol, a WHO-essential drug, as a potentially safe and effective medication for chimeric antigen receptor (CAR) T–induced human cytokine release syndrome (CRS) and demonstrates that metoprolol relieves CRS via an unexpected mechanism of inhibiting IL-6 translation elongation.
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition
In this study, we have discovered that hemifacial myohyperplasia results from a somatic gain-of-function mutation in PI3KCA. Using a new mouse model, we investigated the underlying mechanisms and demonstrated that alpelisib, a pharmacological inhibitor, significantly enhances both the preclinical model and patients.
Defective LAT signalosome pathology in mice mimics human IgG4-related disease at single-cell level
Joachim et al. deciphered via single-cell transcriptomics and functional genomics the etiopathology of a fast-onset mouse autoimmune and inflammatory disorder due to defective LAT signalosomes. It provides a preclinical model for IgG4-related disease, a human autoimmune and inflammatory condition.
NK cell expansion requires HuR and mediates control of solid tumors and long-term virus infection
Piersma et al. identify a crucial role for posttranscriptional regulation by HuR in NK cell proliferation. This study reveals that HuR-dependent NK cell expansion is required for control of long-term virus infection and solid tumors without affecting acute infection or tumor metastases.
Brief Definitive Report
Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer
A preclinical mouse model demonstrates that genetic alterations in the blood system characteristic of clonal hematopoiesis (CH) contribute to an aggressive solid tumor phenotype. It further identifies cancer angiogenesis as a potential therapeutic target to mitigate adverse CH effects.
Interleukin-22 suppresses major histocompatibility complex II in mucosal epithelial cells
IL-22 directly suppresses interferon-γ–induced intestinal and respiratory epithelial cell MHC II. While suppression of IL-22–driven epithelial MHC II may be beneficial in chronic inflammatory conditions, it may increase susceptibility to infection by delaying initiation of appropriate immune responses.
Allergen exposure functionally alters influenza-specific CD4+ Th1 memory cells in the lung
In this study, Rüterbusch et al. report that respiratory exposure to house dust mite allergen or rIL-33 can persistently alter the subsequent functionality of an influenza-specific CD4+ lung TRM population in an antigen-independent, cytokine-dependent manner that impacts disease outcome.
Technical Advances and Resources
Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
Acri and colleagues report transcriptomic responses to tau and elevated tau seeding activity in wild-derived mice relative to C57BL/6J genetic background. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.
Insights
IL-22: Immunity’s bittersweet symphony
Moniruzzaman et al. discovered that interleukin-22 (IL-22) represses MHC class II expression by epithelial cells with an opposite impact on chronic inflammatory disease and viral infection.
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