Commentary
Abstract
Retinitis pigmentosa (RP), the most common form of rod-cone dystrophy, is caused by greater than 3100 mutations in more than 71 genes, many of which are preferentially expressed in rod photoreceptors. Cone death generally follows rod loss regardless of the underlying pathogenic mutation. Preventing the secondary loss of cone photoreceptors would preserve central visual acuity and substantially improve patients’ quality of life. In this issue of the JCI, Wang et al. demonstrate that adeno-associated virus–mediated overexpression of TGF-β1 promoted cone survival and function in 3 distinct RP models with rod-specific mutations. TGF-β1 induces microglia to metabolically tune from a glycolytic phenotype (M1) to an oxidative phenotype (M2), which associates with neuroprotection and the antiinflammatory ecosystem. Consolidating the results of this study with our current understanding of how TGF-β1 regulates microglia polarization, we highlight cell-specific metabolome reprogramming as a promising non–gene-specific therapeutic avenue for inherited retinal degenerations.
Authors
Salvatore Caruso, Joseph Ryu, Peter M.J. Quinn, Stephen H. Tsang
Abstract
Most patients with COVID-19 lack antibody to SARS-CoV-2 in the first 10 days of illness while the virus drives disease pathogenesis. SARS-CoV-2 antibody deficiency in the setting of a tissue viral burden suggests that using an antibody as a therapeutic agent would augment the antiviral immune response. In this issue of the JCI, Wang and collaborators describe the kinetics of viral load and antibody responses of 23 individuals with COVID-19 with mild and severe disease. The researchers found: 1) individuals with mild and severe disease produced neutralizing IgG to SARS-CoV-2 10 days after disease onset; 2) SARS-CoV-2 persisted longer in those with severe disease; and 3) there was cross-reactivity between antibodies to SARS-CoV-1 and SARS-CoV-2, but only antibodies from patients with COVID-19 neutralized SARS-CoV-2. These observations provide important information on the serological response to SARS-CoV-2 of hospitalized patients with COVID-19 that can inform the use of convalescent plasma therapy.
Authors
Arturo Casadevall, Michael J. Joyner, Liise-anne Pirofski
Abstract
The lymph node (LN) is an intriguing site not only for inducing protective effector immunity but also for inducing tolerance against peripherally encountered antigens such as tissue-specific self-antigens that are regionally drained and through draining lymph nodes (DLNs). The dual functions of DLNs in immunity are attributable at least in part to fibroblastic reticular cells (FRCs), which are a major population of the nonhematopoietic compartment in the LN. In this issue of the JCI, Li, Zhao, and colleagues investigated DLNs in the transplantation setting. The authors demonstrated that, following skin transplantation, the donor mast cell–mediated senescence in FRCs was associated with collagen 1 deposition in DLNs. Systemic administration to mice of FRCs that were expanded ex vivo decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data implicate the DLN as a target for immunomodulatory therapy of transplant rejection.
Authors
Zhaoli Sun, James Burdick
Abstract
New York City has been described as the epicenter of the COVID-19 pandemic in the United States. While health care workers are notably at increased risk for COVID-19 infection, the impact on resident physicians remains unclear. In this issue of the JCI, Breazzano et al. surveyed resident physicians for their exposure to COVID-19 during the exponential phase of the COVID-19 pandemic. The researchers also assessed how personal protective equipment (PPE) and COVID-19 testing protected health care workers (HCWs) from infection. This study highlights resident physician experiences of the first COVID-19 wave that can inform and improve preparedness for upcoming COVID-19 surges and other future epidemics.
Authors
Lauren I. Shapiro, Grace R. Kajita, Julia H Arnsten, Yaron Tomer
Abstract
Neuromyelitis optica (NMO) is a central nervous system (CNS) inflammatory autoimmune disease caused by antibodies against aquaporin-4 (AQP4) expressed on astrocytes. Binding of AQP4-specific antibodies (NMO-IgG) triggers activation of the complement cascade, which is responsible for astrocyte loss and secondary demyelination. Although the role for the cytolytic complement proteins in astrocyte destruction in NMO is well established, little is known regarding the initial phase of astrocyte injury. In this issue of the JCI, Chen and colleagues evaluated the precytolytic phase when NMO-IgG binds astrocytes in vivo in the absence of exogenous complement. NMO-IgG alone caused astrocyte activation and AQP4 loss. Surprisingly, microglia, CNS-resident innate immune cells that produce endogenous complement, were required for clinical manifestations of disease, a finding that suggests microglia may serve as a therapeutic target in NMO.
Authors
Zahra Moinfar, Scott S. Zamvil
Abstract
Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular trafficking in immune cells. However, the mechanisms by which Rab27 contributes to airway inflammation and cytokine release remain ambiguous. In this issue of the JCI, Okunishi et al. explored the role that the Rab27 effector, exophilin-5, has in allergic inflammation. Exophilin-5–deficient mice and asthma mouse models revealed that exophilin-5 regulates IL-33 production and the Th2 response. Notably, exophilin-5 deletion enhanced IL-33 release and pathogenic Th2 responsiveness through the mTOR pathway and altered intracellular IL-33 trafficking. This work provides insights into the molecular mechanisms that underlie inflammatory lung disease.
Authors
Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg
Abstract
The mechanism by which maternal obesity influences fetal brain development and behavior is not well understood. In this issue of the JCI, Lippert et al. showed that feeding maternal mice a high-fat diet (HFD) during lactation attenuated the activity of dopamine (DA) midbrain neurons and altered the DA-related behavioral phenotype seen in the offspring. The authors further suggested that the altered excitatory and inhibitory balance between D1 medium spiny neurons (MSN) and D2 MSN mediates this behavioral phenotype. These mechanisms may provide strategies for preventing the negative effects of maternal obesity on offspring development and adult health.
Authors
Yuki Yasumoto, Tamas L. Horvath
Abstract
Mechanical stretch of baroreceptors in the wall of the aortic arch and carotid sinus initiates autonomic reflexes to change heart rate and blood pressure for cardiovascular homeostasis. In this issue of the JCI, Lu et al. show that tentonin 3 (TTN3), a recently identified stretch-sensitive ion channel, was present at the vagus afferent nerve endings innervating the aortic arch to function as a baroreceptor. This study expands the molecular profiles of baroreceptors and provides new insights into molecular mechanisms underlying the regulation of cardiovascular functions through baroreceptor function.
Authors
Jianguo G. Gu, Dan E. Berkowitz
Abstract
Th17 cells (producing IL-17) and Th9 cells (producing IL-9) exhibit functional plasticity, and their role in tumorigenicity is controversial. Th17/IL-17 and Th9/IL-9 exhibit critical, but often opposing, roles in tumor progression. In this issue of the JCI, Salazar et al. show that while IL-17 and IL-9 induced distinct but complementary molecular pathways, both cytokines also induced epithelial-mesenchymal transition (EMT) in lung cancer cells and promoted metastatic spreading. A key question before us now is whether IL-9 and IL-17 contribute to tumor progression in a sequential and stage-specific manner within the tumor microenvironment.
Authors
Chi Yan, Ann Richmond
Abstract
AMPK is a heterotrimeric complex that serves as a major sensor of energy status in eukaryotic cells. Accumulating evidence depicts a complex role of dysregulated AMPK signaling in Alzheimer’s disease (AD). In this issue of the JCI, Zimmermann et al. report on their investigation of AD-specific differential expression of AMPKα1 and AMPKα2 isoforms of the catalytic subunit and demonstrate that genetic reduction of AMPKα1, but not AMPKα2, rescued cognitive decline in AD mouse models. These findings reveal an isoform-specific role of AMPKα in the pathogenesis of AD, which likely provides a more precise target for future therapeutic development.
Authors
Fanpeng Zhao, Chunyu Wang, Xiongwei Zhu
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Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)