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Abstract

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.

Authors

Lukas F. Mager ... Bruce Beutler, Philippe Krebs

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Abstract

The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the ISR inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis — a specialized form of apoptosis — following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HO1 promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-deficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO-1 expression in ATF4-deficient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors.

Authors

Souvik Dey ... J. Alan Diehl, Constantinos Koumenis

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Abstract

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.

Authors

Nils Schallner ... Leo E. Otterbein, Khalid A. Hanafy

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Abstract

The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative μ-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a μ-opioid receptor–deficient mouse that lacks all Oprm1 splice variants, ablating μ-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia.

Authors

Zhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, Ying-Xian Pan

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Abstract

The selective pressure that drives antigenic changes in influenza viruses is thought to originate from the human immune response. Here, we have characterized the B cell repertoire from a previously vaccinated donor whose serum had reduced neutralizing activity against the recently evolved clade 6B H1N1pdm09 viruses. While the response was markedly polyclonal, 88% of clones failed to recognize clade 6B viruses; however, the ability to neutralize A/USSR/90/1977 influenza, to which the donor would have been exposed in childhood, was retained. In vitro selection of virus variants with representative monoclonal antibodies revealed that a single amino acid replacement at residue K163 in the Sa antigenic site, which is characteristic of the clade 6B viruses, was responsible for resistance to neutralization by multiple monoclonal antibodies and the donor serum. The K163 residue lies in a part of a conserved surface that is common to the hemagglutinins of the 1977 and 2009 H1N1 viruses. Vaccination with the 2009 hemagglutinin induced an antibody response tightly focused on this common surface that is capable of selecting current antigenic drift variants in H1N1pdm09 influenza viruses. Moreover, amino acid replacement at K163 was not highlighted by standard ferret antisera. Human monoclonal antibodies may be a useful adjunct to ferret antisera for detecting antigenic drift in influenza viruses.

Authors

Kuan-Ying A. Huang ... Rodney S. Daniels, Alain R. Townsend

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Abstract

μ-Opioid agonists mediate their analgesic effect through GPCRs that are generated via alternate splicing of the Oprm1 transcript. While the majority of μ-opioids interact with receptors comprising the canonical 7 transmembrane (7TM) domain, a recently identified class of μ-opioids appears to require a 6TM domain variant. In this issue of the JCI, Lu and colleagues provide an in vivo proof-of-concept demonstration that a 6TM isoform of the μ-opioid receptor can support functional analgesia in Oprm1-deficent animals. The 6TM isoform was pharmacologically distinct from the canonical 7TM μ-opioid receptor, and 6TM agonists had a reduced side effect profile, which confers a strong therapeutic advantage over standard opioid analgesics. The observations of Lu et al. extend the reach of opioid-receptor neurobiology and pharmacology into a new era of analgesic discovery. This advance emerges from a series of fundamental research analyses in which elements of the endogenous opioid system were frequently in the vanguard.

Authors

Michael J. Iadarola, Matthew R. Sapio, Andrew J. Mannes

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May 2015


125-5-cover

May 2015 Issue

On the cover:
Visualizing tumor-infiltrating T cells

The cover image is a modified 3D reconstruction of an [18F]-L-FMAU PET/CT scan to detect hematopoietic cells labeled with a reporter gene, showing tumor-infiltrating cells within the left flank and engraftment of cells within the BM. On page 1815, McCracken et al. describe a noninvasive technique for visualizing engineered immune cells in multiple mouse models of adoptive cellular immunotherapy.

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Jci_impact_2015_05

May 2015 Impact

JCI Impact is a digest of the research, reviews, and other features published in each month's issue of the Journal of Clinical Investigation.

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Review Series - More

Enteric Nervous System

Series edited by Rodger Liddle

The enteric nervous system (ENS) encompasses extrinsic and intrinsic neurons, glia, and sensory epithelial cells that are embedded throughout the gastrointestinal tract. The circuits formed by these cells are responsible for interpreting sensory information in the gut lumen in order to regulate gut motility, secretion, food intake, and immune function. The ENS communicates with the CNS in a bidirectional manner, allowing stimuli in the gut to influence mood, food intake, and other behaviors. Reviews in this series examine the mechanisms by which the ENS develops from neural crest cells, chemosensory mechanisms that allow for the detection of and response to fats and other nutrients within the gut lumen, the role of the enteric glia, regulation of ENS function by the immune system and inflammation, and the impact of surgery and the gut microbiota on ENS communication with the brain.

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