The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favor the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been demonstrated in humans. Genetic studies of NF-κB signalling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppression of IL-1β expression. Here, we report an infant displaying clinical pathology comprising neutrophil-mediated auto-inflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation in NFKBIA, resulting in a L34P IκBα variant, that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced-pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient’s hyper-IL-1β secretion correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, whilst decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signalling in the prevention of neutrophilic-dependent auto-inflammatory diseases. We showed that IκBα controls IL-1β secretion through a mechanism of self-limiting post-transcriptional regulation. These findings also highlight a therapeutic potential for IL-1 inhibitors to treat complications arising from systemic NF-κB inhibition.
Enrica Ee Kar Tan, Richard Hopkins, Chrissie K. Lim, Saumya Jamuar, Christina Ong, Koh Cheng Thoon, Mark J.A. Koh, Eun Myoung Shin, Derrick Wen Quan Lian, Madhushanee Weerasooriya, Christopher Z.W Lee, Andreas Alvin Purnomo Soetedjo, Chang Siang Lim, Veronica B. Au, WM Edmond Chua, Hui Yin Lee, Leigh Ann Jones, Sharmy Jennifer James, Nivashini Kaliaperumal, Jeffrey Kwok, Ee Shien Tan, Biju Thomas, Lena Ho, Lynn Wu, Anna-Marie Fairhurst, Florent Ginhoux, Adrian K.K. Teo, Yongliang Zhang, Kok Haur Ong, Weimiao Yu, Byrappa Venkatesh, Vinay Tergaonkar, Bruno Reversade, Keh-Chuang Chin, Ah Moy Tan, Woei Kang Liew, John E. Connolly
How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrates that B55ß, a regulatory subunit of the phosphatase PP2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8 T cells. Through the modulation of AKT, B55ß induced the expression of the pro-apoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55ß and Hrk were both required for in vivo and in vitro contraction of activated CD8 lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses, or to promote immune memory.
Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamin García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, Jose C. Crispin
Store-operated calcium entry (SOCE) is the major route of Ca2+ influx in platelets. The Ca2+ sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming puncta structures with the Ca2+ channel Orai1 and the inositol trisphosphate receptor (IP3R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP3R in platelets. Deletion of platelet Bin2 (Bin2fl/fl,Pf4-Cre mice) resulted in reduced Ca2+ store release and Ca2+ influx in response to all tested platelet agonists. These defects were a consequence of impaired IP3R function in combination with defective STIM1-mediated SOC channel activation, while Ca2+ store content and agonist-induced IP3 production were unaltered. These defects translated into impaired thrombus formation under flow and a protection of Bin2fl/fl,Pf4-Cre mice in models of arterial thrombosis and stroke. These results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.
Julia Volz, Charly Kusch, Sarah Beck, Michael Popp, Timo Vögtle, Mara Meub, Inga Scheller, Hannah S. Heil, Julia Preu, Michael K. Schuhmann, Katherina Hemmen, Thomas Premsler, Albert Sickmann, Katrin G. Heinze, David Stegner, Guido Stoll, Attila Braun, Markus Sauer, Bernhard Nieswandt
This Viewpoint describes how physicians and researchers can utilize approaches based on relationship-centered care and structural competence to reduce racism and enhance trustworthiness in health care and biomedical research.
Lisa A. Cooper, Deidra C. Crews
Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these ‘anti-leukocyte’ antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and post-transfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for ‘anti-leukocyte’ antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.
Simon J. Cleary, Nicholas Kwaan, Jennifer J. Tian, Daniel R. Calabrese, Beñat Mallavia, Mélia Magnen, John R. Greenland, Anatoly Urisman, Jonathan P. Singer, Steven R. Hays, Jasleen Kukreja, Ariel M. Hay, Heather L. Howie, Pearl Toy, Clifford A. Lowell, Craig N. Morrell, James C. Zimring, Mark R. Looney
Background: Initial reports from the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to Coronavirus Disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed Multisystem Inflammatory Syndrome in Children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology. Methods: We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8 and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. Cts and burr cells on blood smears also differentiated between patients with severe COVID-19 and those with MIS-C. Conclusion: Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and severe COVID-19.
Caroline Diorio, Sarah E. Henrickson, Laura A. Vella, Kevin O. McNerney, Julie M. Chase, Chakkapong Burudpakdee, Jessica H. Lee, Cristina Jasen, Fran Balamuth, David M. Barrett, Brenda Banwell, Kathrin M. Bernt, Allison M. Blatz, Kathleen Chiotos, Brian T. Fisher, Julie C. Fitzgerald, Jeffrey S. Gerber, Kandace Gollomp, Christopher Gray, Stephan A. Grupp, Rebecca M. Harris, Todd J. Kilbaugh, Audrey R. Odom John, Michele P. Lambert, Emily J. Liebling, Michele Paessler, Whitney Petrosa, Charles A. Phillips, Anne F. Reilly, Neil Romberg, Alix E. Seif, Deborah Sesok-Pizzini, Kathleen Sullivan, Julie Vardaro, Edward M Behrens, David T. Teachey, Hamid Bassiri
Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of anti-oxidant genes by HIF-2. ROS in turn activates chemoreflex and suppresses baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We will also discuss how increased ROS generation by HIF-1 also contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.
Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
As a hallmark of immunological ageing, the low-grade, chronic inflammation with accumulation of effector-memory T cells contributes to the increased susceptibility of many ageing-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how ageing drives regulatory T (Treg) cell ageing and alters their function is not fully understood due to a lack of specific ageing markers. Here, by a combination of cellular, molecular and bioinformatic approaches, we discover that Treg cells senesce more severely than conventional T (Tconv) cells during ageing. We found Treg cells from aged mice were less efficient than young Treg cells to suppress Tconv cell function in an inflammatory-bowel-disease model and to prevent Tconv cell ageing in the irradiation-induced ageing model. Furthermore, we revealed that DCAF1 (DDB1 and CUL4 associated factor 1) was downregulated in aged Treg cells and was critical to restrain Treg cell ageing via glutathione S-transferase P (GSTP1) regulated reactive-oxygen-species (ROS). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Treg cells. Therefore, our studies uncover an important role of DCAF1-GSTP1-ROS axis in Treg cell senescence, which leads to uncontrolled inflammation and immunological ageing.
Zengli Guo, Gang Wang, Bing Wu, Wei-Chun Chou, Liang Cheng, Chenlin Zhou, Jitong Lou, Di Wu, Lishan Su, Junnian Zheng, Jenny Pan-Yun Ting, Yisong Y. Wan
An alarming increase in children presenting with fever, hyperinflammation and multiorgan dysfunction frequently requiring intensive care has been observed after SARS-CoV-2 infection. The illness resembles Kawasaki Disease (KD) with coronary dilatation and aneurysm occurring in some. However, the cardiovascular manifestations were typically on the severe end of the KD spectrum with cardiogenic shock a common presentation together with other features. This led to defining a unique syndrome named multisystem inflammatory syndrome in Children (MIS-C). In this issue of the JCI, Lee and Day-Lewis et al. and Diorio et al. explored the clinical profiles associated with COVID-19 in children. We posit that while splitting MIS-C into a separate disease may aid clinical management decisions, lumping it into the KD pot may better serve to understand pathobiology.
Rae S.M. Yeung, Polly J. Ferguson
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