In the wake of the brutal murders of Ahmaud Arbery, Sean Reed, Breonna Taylor, and George Floyd and, amidst international outcries for social justice, many of us are asking ourselves what we can do to effect change. How can we be impactful allies in the medical profession? How can we support and protect our Black students and foster their careers? This Viewpoint examines the importance of improving diversity and inclusion among physicians and scientists at academic institutions .
Briyana R. Chisholm, Enid R. Neptune, Sherita H. Golden, Linda Resar
The genetic factors that determine a patient’s risk for developing the acute respiratory distress syndrome (ARDS) remain understudied. In this issue of the JCI, Reilly and colleagues analyzed three cohorts of critically-ill patients and observed an association between the ABO allele A1 and the onset of moderate-severe ARDS. This association was most notable in patients with non-pulmonary sepsis (an indirect, vascular-targeted mechanism of lung injury) and persisted in patients who lacked epithelial expression of the A antigen, suggesting an endothelial mechanism of A1-associated ARDS susceptibility. Critically-ill patients with blood type A had increased circulating concentrations of endothelial-derived glycoproteins von Willebrand Factor and soluble thrombomodulin, and marginal lungs from blood type A donors were less likely to recover function during ex vivo perfusion. These findings implicate A antigen glycosylation of endothelial cells as a critical, genetically-determined risk factor for indirect lung injury that may contribute to the mechanistic heterogeneity of ARDS.
Alicia N. Rizzo, Eric P. Schmidt
As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium can also oxidize long-chain fatty acids, and that luminally-delivered acylcarnitines in bile can be consumed via apical absorption by the intestinal epithelium resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.
Sarah A. Smith, Sayaka A. Ogawa, Lillian Chau, Kelly A. Whelan, Kathryn E. Hamilton, Jie Chen, Lu Tan, Eric Z. Chen, Sue Keilbaugh, Franz Fogt, Meenakshi Bewtra, Jonathan Braun, Ramnik J. Xavier, Clary B. Clish, Barry Slaff, Aalim M. Weljie, Frederic D. Bushman, James D. Lewis, Hongzhe Li, Stephen R. Master, Michael J. Bennett, Hiroshi Nakagawa, Gary D. Wu
SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and non-hospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared to healthy and convalescent individuals, with the exception of B lymphocytes which increased. Our findings show increased frequencies of T-cell activation markers (CD69, Ox40, HLA-DR and CD154) in hospitalized patients, with other T-cell activation/exhaustion markers (CD25, PD-L1 and TIGIT) remaining elevated in hospitalized and non-hospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization, followed by an increase in PD1 frequencies in non-hospitalized individuals. Interestingly, many of these changes were found to increase over time in non-hospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation following SARS-CoV-2 infection. Changes in T-cell activation/exhaustion in non-hospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation following SARS-CoV-2 infection highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.
Jacob K. Files, Sushma Boppana, Mildred D. Perez, Sanghita Sarkar, Kelsey E. Lowman, Kai Qin, Sarah Sterrett, Eric Carlin, Anju Bansal, Steffanie Sabbaj, Dustin M. Long, Olaf Kutsch, James Kobie, Paul Goepfert, Nathaniel Erdmann
The regulation of autophagy-dependent lysosome homeostasis in vivo is unclear. We show the inositol polyphosphate 5-phosphatase INPP5K regulates autophagic lysosome reformation (ALR), a lysosome recycling pathway, in muscle. INPP5K hydrolyses phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol 4-phosphate (PI(4)P) and INPP5K mutations cause muscular dystrophy by unknown mechanisms. We report loss of INPP5K in muscle causes severe disease, autophagy inhibition and lysosome depletion. Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k–/– muscle suppresses autophagy and lysosome repopulation via ALR inhibition. Defective ALR in Inpp5k–/– myoblasts was characterised by enlarged autolysosomes and the persistence of hyperextended reformation tubules, structures that participate in membrane-recycling to form lysosomes. Reduced disengagement of the PI(4,5)P2 effector clathrin was observed on reformation tubules which we propose interferes with ALR completion. Inhibition of PI(4,5)P2 synthesis, or expression of wild-type, but not INPP5K-disease mutants in INPP5K-depleted myoblasts restored lysosomal homeostasis. Therefore, bidirectional interconversion of PI(4)P/PI(4,5)P2 on autolysosomes is integral to lysosome replenishment and autophagy function in muscle. Activation of TFEB-dependent de novo lysosome biogenesis did not compensate for loss of ALR in Inpp5k–/– muscle, revealing a dependence on this lysosome recycling pathway. Therefore, in muscle, ALR is indispensable for lysosome homeostasis during autophagy and when defective is associated with muscular dystrophy.
Meagan J McGrath, Matthew J. Eramo, Rajendra Gurung, Absorn Sriratana, Stefan M. Gehrig, Gordon S. Lynch, Sonia Raveena Lourdes, Frank Koentgen, Sandra J. Feeney, Michael Lazarou, Catriona A. McLean, Christina A. Mitchell
Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches to permit non-contact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used seven cell-type specific mouse Cre lines to conditionally knockout Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ bone marrow perivascular cells, Osx+ osteo-progenitor cells (OPCs), Pf4+ megakaryocytes and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9 induced acute myeloid leukemia (AML) as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest that targeting ANGPTL2-SEVs from ECs might be a potential strategy to interfere certain types of AML.
Dan Huang, Guohuan Sun, Xiaoxin Hao, Xiaoxiao He, Zhaofeng Zheng, Chiqi Chen, Zhuo Yu, Li Xie, Shihui Ma, Ligen Liu, Bo O. Zhou, Hui Cheng, Junke Zheng, Tao Cheng
Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients and Zeb1 KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9 and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically co-ordinating HSC self-renewal, apoptotic and multi-lineage differentiation fates required to suppress leukemic potential in AML.
Alhomidi Almotiri, Hamed Ahmad A. Alzahrani, Juan Bautista Menendez-Gonzalez, Ali Abdelfattah, Badi Alotaibi, Lubaid Saleh, Adelle Greene, Mia R. F. Georgiou, Alex Gibbs, Amani Salem Alsayari, Sarab Taha, Leigh-Anne Thomas, Dhruv Shah, Sarah Edkins, Peter J. Giles, Marc P. Stemmler, Simone Brabletz, Thomas Brabletz, Ashleigh S. Boyd, Florian A. Siebzehnrubl, Neil P. Rodrigues
Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in aging and neurodegeneration.
Lily Keane, Ignazio Antignano, Sean-Patrick Riechers, Raphael Zollinger, Anaelle A. Dumas, Nina Offermann, Maria E. Bernis, Jenny Russ, Frederike J. Graelmann, Patrick N. McCormick, Julia Esser, Dario Tejera, Ai Nagano, Jun Wang, Claude Chelala, Yvonne Biederbick, Annett Halle, Paolo Salomoni, Michael Thomas Heneka, Melania Capasso
Available evidence suggests significant heterogeneity in the human immune response to SARS-CoV-2. In this Viewpoint, we examine the spectrum of SARS-CoV-2-associated clinical inflammatory syndromes identified in adult and pediatric populations to date. A better understanding of the immunopathologies and related clinical manifestations of these syndromes is necessary to improve their diagnosis and management.
Jill E. Weatherhead, Eva H. Clark, Tiphanie P. Vogel, Robert L. Atmar, Prathit A. Kulkarni
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome, caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic patient-specific NF1-mutant human induced-pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that while wild-type and heterozygous NF1-mutant hiPSC-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contain the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulate their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that in addition to regulating MAPK-mediated cell growth, NF1 loss also alters Schwann cell differentiation to promote neurofibroma development. Taken together, we established complementary humanized neurofibroma explant and first-in-kind mouse genetically engineered nodular cutaneous neurofibroma models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
Juan Mo, Corina Anastasaki, Zhiguo Chen, Tracey Shipman, Jason B. Papke, Kevin Y. Yin, David H. Gutmann, Lu Q. Le
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