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Abstract
Authors
Barney S. Graham, Kizzmekia S. Corbett
Abstract
β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell–specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with β cell loss, but rather loss of β cell identity. Sel1L-Hrd1 ERAD controlled β cell identity via TGF-β signaling, in part by mediating the degradation of TGF-β receptor 1. Inhibition of TGF-β signaling in Sel1L-deficient β cells augmented the expression of β cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in β cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.
Authors
Neha Shrestha, Tongyu Liu, Yewei Ji, Rachel B. Reinert, Mauricio Torres, Xin Li, Maria Zhang, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Chengyang Liu, Ali Naji, Ming Liu, Jiandie D. Lin, Sander Kersten, Peter Arvan, Ling Qi
Abstract
AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic α subunit exists in 2 isoforms: AMPKα1 and AMPKα2. Recent studies suggest a role of AMPKα overactivation in Alzheimer’s disease–associated (AD-associated) synaptic failure. However, whether AD-associated dementia can be improved by targeting AMPK remains unclear, and roles of AMPKα isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPKα isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPKα repression on AD pathophysiology. We found that repression of AMPKα1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPKα2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry–based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPKα isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPKα1 inhibition. Our findings reveal isoform-specific roles of AMPKα in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes.
Authors
Helena R. Zimmermann, Wenzhong Yang, Nicole P. Kasica, Xueyan Zhou, Xin Wang, Brenna C. Beckelman, Jingyun Lee, Cristina M. Furdui, C. Dirk Keene, Tao Ma
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein–coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
Authors
Pavan Bhargava, Matthew D. Smith, Leah Mische, Emily Harrington, Kathryn C. Fitzgerald, Kyle Martin, Sol Kim, Arthur Anthony Reyes, Jaime Gonzalez-Cardona, Christina Volsko, Ajai Tripathi, Sonal Singh, Kesava Varanasi, Hannah-Noelle Lord, Keya Meyers, Michelle Taylor, Marjan Gharagozloo, Elias S. Sotirchos, Bardia Nourbakhsh, Ranjan Dutta, Ellen M. Mowry, Emmanuelle Waubant, Peter A. Calabresi
Abstract
The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.
Authors
Bo Hu, Xiao Lv, Hao Chen, Peng Xue, Bo Gao, Xiao Wang, Gehua Zhen, Janet L. Crane, Dayu Pan, Shen Liu, Shuangfei Ni, Panfeng Wu, Weiping Su, Xiaonan Liu, Zemin Ling, Mi Yang, Ruoxian Deng, Yusheng Li, Lei Wang, Ying Zhang, Mei Wan, Zengwu Shao, Huajiang Chen, Wen Yuan, Xu Cao
Abstract
Alloantibodies in presensitized transplant candidates deposit complement membrane attack complexes (MACs) on graft endothelial cells (ECs), increasing risk of CD8+ T cell–mediated acute rejection. We recently showed that human ECs endocytose MACs into Rab5+ endosomes, creating a signaling platform that stabilizes NF-κB–inducing kinase (NIK) protein. Endosomal NIK activates both noncanonical NF-κB signaling to synthesize pro–IL-1β and an NLRP3 inflammasome to process and secrete active IL-1β. IL-1β activates ECs, increasing recruitment and activation of alloreactive effector memory CD4+ T (Tem) cells. Here, we report that IFN-γ priming induced nuclear expression of IL-15/IL-15Rα complexes in cultured human ECs and that MAC-induced IL-1β stimulated translocation of IL-15/IL-15Rα complexes to the EC surface in a canonical NF-κB–dependent process in which IL-15/IL-15Rα transpresentation increased activation and maturation of alloreactive CD8+ Tem cells. Blocking NLRP3 inflammasome assembly, IL-1 receptor, or IL-15 on ECs inhibited the augmented CD8+ Tem cell responses, indicating that this pathway is not redundant. Adoptively transferred alloantibody and mouse complement deposition induced IL-15/IL-15Rα expression by human ECs lining human coronary artery grafts in immunodeficient mice, and enhanced intimal CD8+ T cell infiltration, which was markedly reduced by inflammasome inhibition, linking alloantibody to acute rejection. Inhibiting MAC signaling may similarly limit other complement-mediated pathologies.
Authors
Catherine B. Xie, Bo Jiang, Lingfeng Qin, George Tellides, Nancy C. Kirkiles-Smith, Dan Jane-wit, Jordan S. Pober
Abstract
Plasmacytoid DCs (pDCs), the major producers of type I interferon, are principally recognized as key mediators of antiviral immunity. However, their role in tumor immunity is less clear. Depending on the context, pDCs can promote or suppress antitumor immune responses. In this study, we identified a naturally occurring pDC subset expressing high levels of OX40 (OX40+ pDC) enriched in the tumor microenvironment (TME) of head and neck squamous cell carcinoma. OX40+ pDCs were distinguished by a distinct immunostimulatory phenotype, cytolytic function, and ability to synergize with conventional DCs (cDCs) in generating potent tumor antigen–specific CD8+ T cell responses. Transcriptomically, we found that they selectively utilized EIF2 signaling and oxidative phosphorylation pathways. Moreover, depletion of pDCs in the murine OX40+ pDC–rich tumor model accelerated tumor growth. Collectively, we present evidence of a pDC subset in the TME that favors antitumor immunity.
Authors
Kate Poropatich, Donye Dominguez, Wen-Ching Chan, Jorge Andrade, Yuanyuan Zha, Brian Wray, Jason Miska, Lei Qin, Lisa Cole, Sydney Coates, Urjeet Patel, Sandeep Samant, Bin Zhang
Abstract
Authors
Maximilian F. Konig, Mike Powell, Verena Staedtke, Ren-Yuan Bai, David L. Thomas, Nicole Fischer, Sakibul Huq, Adham M. Khalafallah, Allison Koenecke, Ruoxuan Xiong, Brett Mensh, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Joshua T. Vogelstein, Susan Athey, Shibin Zhou, Chetan Bettegowda
Abstract
Authors
Mark Donowitz, Jerrold R. Turner, Alan S. Verkman, Nicholas Constantine Zachos
Abstract
The absence of alloantibodies is a feature of transplantation tolerance. Although the lack of T cell help has been evoked to explain this absence, herein we provide evidence for B cell–intrinsic tolerance mechanisms. Using a murine model of heart tolerance, we showed that alloreactive B cells were not deleted but rapidly lost their ability to differentiate into germinal center B cells and secrete donor-specific antibodies. We inferred that tolerant alloreactive B cells retained their ability to sense alloantigen because they continued to drive T cell maturation into CXCR5+PD-1+ T follicular helper cells. Unexpectedly, dysfunctional alloreactive B cells acquired the ability to inhibit antibody production by new naive B cells in an antigen-specific manner. Thus, tolerant alloreactive B cells contribute to transplantation tolerance by foregoing germinal center responses while retaining their ability to function as antigen-presenting cells and by actively suppressing de novo alloreactive B cell responses.
Authors
Stella H.W. Khiew, Dharmendra Jain, Jianjun Chen, Jinghui Yang, Dengping Yin, James S. Young, Alexander Dent, Roger Sciammas, Maria-Luisa Alegre, Anita S. Chong
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
Abstract
Since it was shown in the early 1950s that it is possible to induce transplantation tolerance in neonates, immune tolerance strategies have been actively pursued. It was found that T cells play a critical role in graft rejection, but can also be major players in mediating transplantation tolerance. Consequently, many experimental systems focused on T cells, often with a complete exclusion of B cells from in vivo animal models. It is now becoming clear that in addition to T cells, B cells can mediate graft rejection and transplantation tolerance. In this issue of the JCI, Khiew et al. investigated the contribution of alloreactive B cells to transplantation tolerance using a mouse cardiac transplantation model. The authors revealed a distinct tolerant B cell phenotype possessing the ability to suppress naive B cells. These data lead to a better understanding of B cell contributions to transplantation tolerance, and may inform the development of future immune tolerance protocols.
Authors
Luis Graca
Abstract
Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression.
Authors
Wenqiang Cao, Fengqin Fang, Timothy Gould, Xuanying Li, Chulwoo Kim, Claire Gustafson, Simon Lambert, Cornelia M. Weyand, Jörg J. Goronzy
Abstract
The atypical cadherin FAT4 has established roles in the regulation of planar cell polarity and Hippo pathway signaling that are cell context dependent. The recent identification of FAT4 mutations in Hennekam syndrome, features of which include lymphedema, lymphangiectasia, and mental retardation, uncovered an important role for FAT4 in the lymphatic vasculature. Hennekam syndrome is also caused by mutations in collagen and calcium binding EGF domains 1 (CCBE1) and ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3), encoding a matrix protein and protease, respectively, that regulate activity of the key prolymphangiogenic VEGF-C/VEGFR3 signaling axis by facilitating the proteolytic cleavage and activation of VEGF-C. The fact that FAT4, CCBE1, and ADAMTS3 mutations underlie Hennekam syndrome suggested that all 3 genes might function in a common pathway. We identified FAT4 as a target gene of GATA-binding protein 2 (GATA2), a key transcriptional regulator of lymphatic vascular development and, in particular, lymphatic vessel valve development. Here, we demonstrate that FAT4 functions in a lymphatic endothelial cell–autonomous manner to control cell polarity in response to flow and is required for lymphatic vessel morphogenesis throughout development. Our data reveal a crucial role for FAT4 in lymphangiogenesis and shed light on the mechanistic basis by which FAT4 mutations underlie a human lymphedema syndrome.
Authors
Kelly L. Betterman, Drew L. Sutton, Genevieve A. Secker, Jan Kazenwadel, Anna Oszmiana, Lillian Lim, Naoyuki Miura, Lydia Sorokin, Benjamin M. Hogan, Mark L. Kahn, Helen McNeill, Natasha L. Harvey
Abstract
Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophil-specific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3F-mediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution.
Authors
Tracie Plant, Suttida Eamsamarng, Manuel A. Sanchez-Garcia, Leila Reyes, Stephen A. Renshaw, Patricia Coelho, Ananda S. Mirchandani, Jessie-May Morgan, Felix E. Ellett, Tyler Morrison, Duncan Humphries, Emily R. Watts, Fiona Murphy, Ximena L. Raffo-Iraolagoitia, Ailiang Zhang, Jenna L. Cash, Catherine Loynes, Philip M. Elks, Freek Van Eeden, Leo M. Carlin, Andrew J.W. Furley, Moira K.B. Whyte, Sarah R. Walmsley
Abstract
Authors
Arthur L. Caplan, Ross Upshur
Abstract
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV–coinfected persons.
Authors
Xiaoming Cheng, Takuro Uchida, Yuchen Xia, Regina Umarova, Chun-Jen Liu, Pei-Jer Chen, Anuj Gaggar, Vithika Suri, Marcus M. Mücke, Johannes Vermehren, Stefan Zeuzem, Yuji Teraoka, Mitsutaka Osawa, Hiroshi Aikata, Keiji Tsuji, Nami Mori, Shuhei Hige, Yoshiyasu Karino, Michio Imamura, Kazuaki Chayama, T. Jake Liang
Abstract
Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01-susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 μg/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.
Authors
Evan M. Cale, Hongjun Bai, Meera Bose, Michael A. Messina, Donn J. Colby, Eric Sanders-Buell, Bethany Dearlove, Yifan Li, Emily Engeman, Daniel Silas, Anne Marie O’Sullivan, Brendan Mann, Suteeraporn Pinyakorn, Jintana Intasan, Khunthalee Benjapornpong, Carlo Sacdalan, Eugène Kroon, Nittaya Phanuphak, Robert Gramzinski, Sandhya Vasan, Merlin L. Robb, Nelson L. Michael, Rebecca M. Lynch, Robert T. Bailer, Amélie Pagliuzza, Nicolas Chomont, Amarendra Pegu, Nicole A. Doria-Rose, Lydie Trautmann, Trevor A. Crowell, John R. Mascola, Jintanat Ananworanich, Sodsai Tovanabutra, Morgane Rolland, on behalf of the RV397 Study Group
Abstract
Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel–deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell–intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel–overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.
Authors
Maike Kober-Hasslacher, Hyunju Oh-Strauß, Dilip Kumar, Valeria Soberon, Carina Diehl, Maciej Lech, Thomas Engleitner, Eslam Katab, Vanesa Fernández-Sáiz, Guido Piontek, Hongwei Li, Björn Menze, Christoph Ziegenhain, Wolfgang Enard, Roland Rad, Jan P. Böttcher, Hans-Joachim Anders, Martina Rudelius, Marc Schmidt-Supprian
Abstract
BACKGROUND Insulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODS A hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTS Insulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSION Hyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver’s maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATION ClinicalTrials.gov NCT02706262.FUNDING NIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.
Authors
Gordon I. Smith, David C. Polidori, Mihoko Yoshino, Monica L. Kearney, Bruce W. Patterson, Bettina Mittendorfer, Samuel Klein
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Abstract
Background: Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Anti-viral immune response is crucial to achieve pathogen clearance, however in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options. Methods: We performed a flow cytometric characterization of immune cells subsets from 30 COVID-19 patients and correlated these data with clinical outcomes. Results: COVID-19 patients showed decreased numbers of circulating T, B and NK cells, and exhibited a skewing of CD8+ T cells towards a terminally differentiated/senescent phenotype. In agreement, T CD4+, T CD8+ but also NK cells displayed reduced anti-viral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in COVID-19 patients, particularly in those that required intensive care. The latter group of patients showed also increased serum IL-6 levels, that correlated to the frequency of granzyme-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells. Conclusion: In conclusion, the association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore anti-viral mechanisms. Funding: This study was supported by funds of Dept. of Experimental and Clinical Medicine of University of Florence (ex-60%) derived from Ministero dell’Istruzione, dell’Università e della Ricerca (Italy).
Authors
Alessio Mazzoni, Lorenzo Salvati, Laura Maggi, Manuela Capone, Anna Vanni, Michele Spinicci, Jessica Mencarini, Roberto Caporale, Benedetta Peruzzi, Alberto Antonelli, Michele Trotta, Lorenzo Zammarchi, Luca Ciani, Leonardo Gori, Chiara Lazzeri, Andrea Matucci, Alessandra Vultaggio, Oliviero Rossi, Fabio Almerigogna, Paola Parronchi, Paolo Fontanari, Federico Lavorini, Adriano Peris, Gian Maria Rossolini, Alessandro Bartoloni, Sergio Romagnani, Francesco Liotta, Francesco Annunziato, Lorenzo Cosmi
Abstract
Background From March 2-April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize COVID-19 impact on NYC resident physicians. Methods IRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors (PDs) April 3–12, 2020, encompassing events from March 2–April 12, 2020. Results From an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2,306 residents. 45.1% of programs reported at least one resident with confirmed COVID-19: 101 resident physicians were confirmed COVID-19-positive, with an additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. Two COVID-19-positive residents were hospitalized, with one in intensive care. Among specialties with >100 residents represented, negative binomial regression indicated that infection risk differed by specialty (p=0.039). 80% of programs reported quarantining a resident. 90/91 programs reported reuse or extended mask use, and 43 programs reported that personal protective equipment (PPE) was suboptimal. 65 programs (74.7%) have redeployed residents elsewhere to support COVID-19 efforts. Conclusion Many resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty. Funding AHA, MPB, RWSC, CGM, LRDG, JDH: NEI Core Grant P30EY019007, RPB Unrestricted Grant. ACP and JS: Parker Family Chair. SXX: University of Pennsylvania.
Authors
Mark P. Breazzano, Junchao Shen, Aliaa H. Abdelhakim, Lora Dagi Glass, Jason Horowitz, Sharon X. Xie, C. Gustavo De Moraes, Alice Chen-Plotkin, Royce W.S. Chen
Abstract
In COVID-19, complement activation may contribute to hemostatic activation leading to pathological features such as microvascular injury and coagulopathy.
Authors
Wen-Chao Song, Garret A. FitzGerald
Abstract
Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy, characterized by a pathognomonic hindbrain malformation. All known JBTS-genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we use the recently identified JBTS-associated protein ARMC9 in tandem-affinity purification and yeast two-hybrid screens to identify a novel ciliary module whose dysfunction underlies JBTS. In addition to known JBTS-associated proteins CEP104 and CSPP1, we identify CCDC66 and TOGARAM1 as ARMC9 interaction partners. We show that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses and characterization of patient-derived fibroblasts, CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrate that dysfunction of ARMC9 or TOGARAM1 results in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant cold- and serum-induced ciliary loss in both ARMC9 and TOGARAM1 patient cell lines suggests a role for this new JBTS-associated protein module in ciliary stability.
Authors
Brooke L. Latour, Julie C. Van De Weghe, Tamara D.S. Rusterholz, Stef J.F. Letteboer, Arianna Gomez, Ranad Shaheen, Matthias Gesemann, Arezou Karamzade, Mostafa Asadollahi, Miguel Barroso-Gil, Manali Chitre, Megan E. Grout, Jeroen van Reeuwijk, Sylvia E.C. van Beersum, Caitlin V. Miller, Jennifer C. Dempsey, Heba Morsy, Michael J. Bamshad, Deborah A. Nickerson, Stephan C.F. Neuhauss, Karsten Boldt, Marius Ueffing, Mohammad Keramatipour, John A. Sayer, Fowzan S. Alkuraya, Ruxandra Bachmann-Gagescu, Ronald Roepman, Dan Doherty
Abstract
The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene expression program in the cysts. We confirmed expression of FOXA1, FOXJ1 and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes, and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
Authors
Michelle L. Brinkmeier, Hironori Bando, Adriana C. Camarano, Shingo Fujio, Koji Yoshimoto, Flávio S. J. de Souza, Sally A. Camper
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May 2020
May 2020 Issue
On the cover:
Qki-activated lipid metabolism preserves myelin integrity
In multiple sclerosis and other demyelinating diseases, reductions in axon-insulating myelin impair the propagation of electrical impulses within the CNS. Although myelin is thought to undergo little turnover in the adult brain, increasing evidence points to the importance of active metabolic processes in myelin integrity. In this issue, Zhou et al. reveal that the oligodendrocyte protein Qki regulates lipid metabolism to support myelin maintenance in adult mice. Oligodendrocyte-specific depletion of Qki reduced the levels of myelin-associated lipids and was associated with rapid demyelination and the development of neurological deficits. These effects of Qki loss were mitigated by high-fat diet or treatment with agonists of the PPARβ-RXRα complex, which controls lipid metabolic gene transcription. These insights provide rationale for further study of lipid metabolism in demyelinating disorders. The cover image depicts myelin sheaths (in green) with active lipid supply from oligodendrocytes and an oligodendrocyte (in yellow) without proper lipid supply. Image credit: Ella Maru Studio.
JCI This Month
May 2020 JCI This Month
JCI This Month is a digest of the research, reviews, and other features published each month.
Review Series - More
Series edited by Leo Luznik
Immunotherapy in Hematological Cancers
Series edited by Leo Luznik
Immunotherapeutic strategies leveraging the immune system’s antitumor activity have become a mainstay of cancer treatment. Strategies including antibody-directed approaches, stem cell transplantation, immunomodulatory drugs, immune checkpoint inhibitors, CAR T cells, and vaccines have demonstrated particular success in controlling and even eradicating hematological cancers. This Review Series, developed by JCI’s associate editor Leo Luznik, discusses ongoing progress in immunotherapeutic targeting of hematological cancers. Reviews will address the state-of-the-art in immunotherapies for acute myeloid leukemia, multiple myeloma, and lymphoma and highlight recent successes and challenges in clinical trials for these diseases; take a detailed look at recent developments in CAR T therapies for B cell malignancies; and describe how personalized antigen targeting can be applied to immunotherapeutic treatment of blood malignancies.
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Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)