The use of broad-spectrum antibiotics in empirical antimicrobial therapy is a lifesaving strategy for patients in intensive care. At the same time, antibiotics dramatically increase the risk for nosocomial infections, such as hospital‑acquired pneumonia caused by Pseudomonas aeruginosa, and other antibiotic-resistant bacteria. In this issue of the JCI, Robak and colleagues identified a mechanism by which depletion of resident gut and lung microbiota by antibiotic treatment results in secondary IgA deficiency and impaired anti–P. aeruginosa host defense. Impaired defenses could be improved by substitution of polyclonal IgA via the intranasal route in a mouse model of pneumonia. Importantly, antibiotic treatment caused lung IgA deficiency that involved reduced TLR-dependent production of a proliferation-inducing ligand (APRIL) and B cell–activating factor (BAFF) in intensive care unit patients. These patients might therefore benefit from future strategies to increase pulmonary IgA levels.
Juergen Lohmeyer, Rory E. Morty, Susanne Herold
Brown et al. report that two weeks of exogenous leptin administration to leptin-naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions.
Michael Rosenbaum, Rudolph L. Leibel
Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein–coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.
Lintao Qu, Michael J. Caterina
Langerhans cells (LCs) are likely among the first targets of HIV-1 infection due to their localization in mucosal tissues. In their recent work, Pena-Cruz and colleagues were able to study HIV-1 infection in vaginal epithelial DCs (VEDCs), termed CD1a+ VEDCs. They show that VEDCs are distinct from other blood- and tissue-derived DCs or LCs because they express the protein langerin but not the lectin receptor DC-SIGN, and they do not have Birbeck granules. The results from this study indicate that HIV-1 using CXCR4 replicates poorly in VEDCs but that a higher replication for HIV-1 using CCR5 strains is supported by VDECs. Furthermore, Pena-Cruz and colleagues demonstrate that VDECs can represent a viral reservoir in HIV-1–infected virologically suppressed women. As such, VDECs may represent another sanctuary of viral persistence and can be an additional obstacle to viral eradication.
Stephan Caucheteux, Vincent Piguet
Crescentic glomerulonephritis, a complication of severe immune glomerular injury, is the pathological correlate of rapidly progressive glomerulonephritis, mediated by both humoral and cellular effectors. In the current issue of the JCI, Chen et al. have implicated Bowman’s capsule in functionally isolating potentially immune effectors, specifically antigen-specific CD8+ T lymphocytes, from podocytes. They suggest that, in crescentic glomerulonephritis, immune-mediated glomerular endothelial injury results in inside-out injury to the glomerulus, with subsequent leukocyte migration through a weakened or ruptured Bowman’s capsule, resulting in outside-in injury. Effector T cells then recognize nephritogenic antigens presented by podocytes or other cells within the urinary space, enhancing injury and crescent formation.
A. Richard Kitching, Maliha A. Alikhan
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a genetic autoimmune disorder that results from gain-of-function mutations in the gene encoding chemokine receptor CXCR4. A previous study characterized a patient with WHIM who underwent a chromothriptic event that resulted in spontaneous deletion of the WHIM allele in a single hematopoietic stem cell and subsequent cure of the disease. In this issue of the JCI, Gao et al. extend this work and show that Cxcl4-haplosufficient bone marrow has a selective advantage for long-term engraftment in murine WHIM models. Moreover, successful engraftment occurred without prior conditioning of recipients. Together, these results have important implications for improving hematopoietic stem/progenitor cell transplant not only for patients with WHIM but also for all patients who may require the procedure.
Hal E. Broxmeyer
The hemostatic response to vascular injury culminates in a fibrin clot network that forms an initial barrier to blood loss and also contributes to microbial host defense. Fibrinogen is cleaved by thrombin into fibrin monomers that spontaneously polymerize into protofibrils and form the extensive fiber networks characteristic of blood clots. In this issue of the JCI, Macrae and colleagues characterize an alternative fibrin structure in which fibrinogen and fibrin assemble into a continuous 2D film at the exterior face of the fibrin clot network. Fibrin films connect to the underlying fiber network through tethering fibers and provide a protective barrier to microbial infiltration. These findings shed new light on a previously overlooked mechanism of fibrin assembly at the clot surface and provide a link between hemostasis and innate immunity.
Sean X. Gu, Steven R. Lentz
The ability to recognize and avoid noxious stimuli is essential for survival. The factors that determine whether a given stimulus is considered positive or negative are complex and not fully understood. In this issue of the JCI, Klawonn and colleagues demonstrate that melanocortin 4 receptor (MC4R) signaling is critical for proper responses to negative stimuli. Mice lacking MC4R were shown to have a surprising preference for aversive stimuli compared with WT animals. Moreover, the authors provide evidence that avoidance behaviors are mediated by hypothalamic POMC neurons signaling to striatal dopamine D1 receptor–expressing medium spiny neurons. Together, these results provide important insight into the regulation of responses to aversive stimuli.
Alexandra G. DiFeliceantonio, Paul J. Kenny
Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.
Hal M. Hoffman, Lori Broderick
Stromal cells within the tumor microenvironment play a supportive role in tumor growth, progression, and treatment resistance; therefore, these nonmalignant cells are potential therapeutic targets. In this issue of the JCI, Szot et al. devised a strategy to exploit the cell-surface marker TEM8 (also known as ANTXR1), which is expressed by cancer-associated stromal cells, as a zip code to deliver an antibody-drug conjugate (ADC) linked to the potent cancer-killing drug monomethyl auristatin E (MMAE). In preclinical tumor and experimental metastasis models of multiple cancer types, TEM8-ADC targeted TEM8-expressing cancer-associated stromal cells, which processed and liberated membrane-permeable MMAE and released this drug via the P-glycoprotein (P-gp) drug transporter. Released MMAE killed cancer cells through a bystander mechanism that did minimal damage to the stromal cells themselves. P-gp–expressing tumor cells displayed MMAE resistance, suggesting that P-gp expression status may identify patients who might benefit the most from TEM8-ADC. This strategy, termed DAaRTS (drug activation and release through stroma), represents an elegant example of how selective expression of a cell-surface molecule on cancer-associated stroma can be exploited to facilitate drug delivery and shrink solid tumors.
James V. McCann, Jamie L. Null, Andrew C. Dudley
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