Retinoic acid (RA) signaling is involved in various physiological and pathological conditions, including development, tumorigenesis, inflammation, and tissue damage and repair. In kidneys, the beneficial effect of RA has been reported in multiple disease models, such as glomerulosclerosis, renal fibrosis, and acute kidney injury. In this issue of the JCI, Chen et al. report a pathway activated by RA signaling that is mediated by the retinoic acid receptor responder protein 1 (RARRES1). Specifically, RARRES1, which is proteolytically cleaved to release the extracellular domain, was endocytosed by podocytes to induce apoptosis and glomerular dysfunction kidney disease. These findings unveil the contrasting aspects, a Janus face, of RA signaling that may guide its therapeutic use.
Qingqing Wei, Zheng Dong
NK cells are responsible for defense against viral infections and cancer. Although activated NK cells are armed to combat tumors, the tumor microenvironment (TME) contains ROS, which suppress NK cell antitumor activity. In this issue of the JCI, Yang, Neo, and colleagues explored NK cell resistance to oxidative stress in vitro and in human non–small-cell lung cancer (NSCLC). High surface thiol density and elevated expression of the ROS scavenger thioredoxin (Trx1) protected NK cells from ROS. Trx1 and thiol levels were higher in IL-15– than in IL-2–primed NK cells. Tumor-infiltrating Trx1+ NK cells were present in patients with NSCLC with elevated ROS levels in the tumor. Smokers scored higher for the ROS signature, which predicted poor prognosis, compared with nonsmokers. This study explains how activated NK cells survive in the ROS-rich TME and suggests that smokers with lung cancer may benefit from therapies using IL-15–primed NK cells.
Theresa L. Whiteside
In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have also been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem- and multiorgan-inflammatory response that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros et al., is one such team who report that the complement system plays a substantial role in creating the hyper-inflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors presented empirical evidence showing that treatment with the complement inhibitor, compstatin Cp-40, inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggests that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19 induced inflammation.
Berhane Ghebrehiwet, Ellinor I. Peerschke
People with COVID-19 can develop pneumonia and severe inflammatory response with excessive cytokine release known as the cytokine storm. The Janus kinase inhibitor baricitinib used to treat rheumatoid arthritis reduces inflammation by modifying the cytokine pathway. In this issue of the JCI, Bronte and Ugel et al. performed an observational longitudinal study to evaluated the use of baricitinib in 20 patients with COVID-19. Treated subjects showed reduced levels of plasma interleukin (IL)-6, tumor necrosis factor (TNF), IL-1β and phosphorylated STAT3 and swift lymphocyte restoration. Notably, these patients had a dramatically favorable clinical outcome. While bias can plague uncontrolled research, this study has biological credibility and warrants randomized control studies.
David L. Thomas
Idiopathic CD4+ T cell lymphocytopenia (ICL) is a heterogeneous syndrome presenting with persistent CD4+ T cell lymphopenia of unknown origin, and opportunistic infections in some patients. The underlying pathogenesis and appropriate management remain understudied. In this issue of the JCI, Perez-Diez and Wong et al. assessed the prevalence of autoantibodies from the sera of 51 adult ICL patients (out of a cohort of 72). Some patients showed high levels of IgG and IgM autoantibodies against numerous autoantigens, and some autoantibodies were specific for lymphocytes. The researchers implicate these autoantibodies as a possible pathogenic mechanism responsible for the reduction in circulating CD4+ T cells. This study goes beyond defining a mechanism in a complex, poorly defined disease; it also brings a renewed focus on ICL that will likely result in improved diagnostic evaluation and treatment.
Jose S. Campos, Sarah E. Henrickson, Roshini S. Abraham
The right ventricle (RV) is involved in systemic circulation in the fetal mammalian heart but quickly transitions to being solely responsible for pulmonary circulation after birth when the left ventricle (LV) becomes the systemic ventricle. To handle the increased workload, LV growth greatly outpaces that of the RV during postnatal stages. However, the molecular basis for this differential growth pattern between the 2 chambers is largely unknown. In this issue of the JCI, Yokota et al. reveal that the p38 mitogen-activated protein kinase (MAPK)/IRE1α/XBP1 axis specifically controls postnatal RV growth by suppressing cell cycle regulatory genes.
Tongbin Wu, Ju Chen
Even with treatment of HIV with antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation remains higher in HIV-infected than HIV-uninfected persons. In this issue of the JCI, Ganatra et al. explored TB reactivation in the context of ART using TB and simian immunodeficiency virus–coinfected (TB/SIV-coinfected) nonhuman primates. The authors found that treating rhesus macaques with ART restored CD4+ T cells in whole blood, spleen, and bronchoalveolar lavage (BAL) fluid, but not in the lung interstitium. TB risk was not decreased in the coinfected macaques treated with ART for 14–63 days, suggesting that ART does not decrease the short-term risk of reactivation. Reactivation occurred as CD4+ T cells were increasing, which is consistent with observations made in humans. This study provides a potential model for systematic evaluation of TB/SIV coinfection and different treatment regimens and strategies to prevent TB reactivation.
Timothy R. Sterling, Philana Ling Lin
The tight junction protein claudin-2 is upregulated in inflammatory bowel disease, and yet its deficit worsens infectious and chemical colitis. In this issue of the JCI, Raju and Shashikanth et al. examined the contribution of claudin-2 to immune-mediated colitis. The authors used transgenic mouse models to show that claudin-2 deficiency attenuated colitis progression as well as a leak barrier defect, albeit at the risk of intestinal obstruction. Further, inhibition of claudin-2 by targeting casein kinase 2 (CK2) also ameliorated colitis. The findings reveal unsuspected links between the pore and leak pathways of intestinal permeability and immune responses leading to colitis. They additionally suggest potential targets for therapeutic intervention in inflammatory bowel disease.
Kim E. Barrett
Bacillus Calmette-Guérin (BCG) vaccination induces variable protection against pulmonary tuberculosis (TB), and a more effective TB vaccine is needed. The potential for BCG to provide protection against heterologous infections, by induction of innate immune memory, is increasingly recognised. These non-specific responses may substantially benefit public health, but are also variable. In this issue of the JCI, Koeken and de Bree et al. report that BCG reduces circulating inflammatory markers in males but not in females, whilst de Bree and Mouritis et al. describe how diurnal rhythms affect the degree of BCG-induced innate memory. These studies further delineate factors that influence the magnitude of responses to BCG and may be crucial to harnessing its potential benefits.
Sarah Prentice, Hazel M. Dockrell
Orexin/hypocretin neurons located in the lateral hypothalamus play a critical role in the maintenance of arousal and contribute to the regulation of multiple homeostatic and behavioral processes. In this issue of the JCI, Tan and Hang et al. report that feeding a high-fat diet to mice compromised the function of the orexin system, leading to impairments in reward-seeking and active coping mechanisms. The researchers observed changes at the cellular and circuit levels suggesting that reduced excitability of orexin neurons affects behavior through induction of a hypoarousal state.
Natalie J. Michael, Joel K. Elmquist
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