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Enhanced Expression of Catalase in Mitochondria Modulates NF-κB-Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages.
Han W, Fessel JP, Sherrill T, Kocurek EG, Yull FE, Blackwell TS
(2020) J Immunol 205: 1125-1134
Show Abstract · Added July 28, 2020
NF-κB is a reduction-oxidation-sensitive transcription factor that plays a key role in regulating the immune response. In these studies, we intended to investigate the role of mitochondrial-derived reactive oxygen species in regulating NF-κB activation by studying transgenic mice that overexpress mitochondrial-targeted human catalase (mCAT). We treated wild-type (WT) and mCAT mice with intratracheal instillation of LPS and found that mCAT mice had exaggerated NF-κB activation in the lungs, increased neutrophilic alveolitis, and greater lung inflammation/injury compared with WT mice. Additional studies using bone marrow chimeras revealed that this hyperinflammatory phenotype was mediated by immune/inflammatory cells. Mechanistic studies using bone marrow-derived macrophages (BMDMs) showed that LPS treatment induced a sustained increase in NF-κB activation and expression of NF-κB-dependent inflammatory mediators in mCAT BMDMs compared with WT BMDMs. Further investigations showed that cytoplasmic, but not mitochondrial, hydrogen peroxide levels were reduced in LPS-treated mCAT BMDMs. However, mCAT macrophages exhibited increased glycolytic and oxidative metabolism, coupled with increased ATP production and an increased intracellular NADH/NAD ratio compared with BMDMs from WT mice. Treatment of BMDMs with lactate increased the intracellular NADH/NAD ratio and upregulated NF-κB activation after LPS treatment, whereas treatment with a potent inhibitor of the mitochondrial pyruvate carrier (UK5099) decreased the NADH/NAD ratio and reduced NF-κB activation. Taken together, these findings point to an increased availability of reducing equivalents in the form of NADH as an important mechanism by which metabolic activity modulates inflammatory signaling through the NF-κB pathway.
Copyright © 2020 by The American Association of Immunologists, Inc.
1 Communities
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0 MeSH Terms
Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.
Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, Olivares-Villagómez D
(2020) J Immunol 204: 1968-1981
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Epithelium, Female, Homeostasis, Humans, Hyaluronan Receptors, Intestines, Intraepithelial Lymphocytes, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Osteopontin, Receptors, Antigen, T-Cell, gamma-delta, Th17 Cells
Show Abstract · Added February 28, 2020
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ, TCRβCD4, TCRβCD4CD8α, and TCRβCD8αα cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ IEL, TCRβ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.
Copyright © 2020 by The American Association of Immunologists, Inc.
1 Communities
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17 MeSH Terms
Regulation of Diabetogenic Immunity by IL-15-Activated Regulatory CD8 T Cells in Type 1 Diabetes.
Stocks BT, Wilson CS, Marshall AF, Hoopes EM, Moore DJ
(2019) J Immunol 203: 158-166
MeSH Terms: Adoptive Transfer, Animals, B-Lymphocytes, CD8 Antigens, Cells, Cultured, Diabetes Mellitus, Type 1, Disease Models, Animal, Humans, Immunotherapy, Adoptive, Interleukin-15, Macrophages, Mice, Mice, Inbred NOD, NK Cell Lectin-Like Receptor Subfamily A, T-Lymphocytes, Regulatory
Show Abstract · Added May 28, 2019
Unchecked collaboration between islet-reactive T and B lymphocytes drives type 1 diabetes (T1D). In the healthy setting, CD8 T regulatory cells (Tregs) terminate ongoing T-B interactions. We determined that specific CD8 Tregs from NOD mice lack suppressive function, representing a previously unreported regulatory cell deficit in this T1D-prone strain. NOD mice possess 11-fold fewer Ly-49 CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and leaves them unable to regulate CD4 T follicular helper cells. As IL-15 is required for Ly-49 CD8 Treg development, we determined that NOD macrophages inadequately -present IL-15. Despite reduced IL-15 -presentation, NOD Ly-49 CD8 Tregs can effectively transduce IL-15-mediated survival signals when they are provided. Following stimulation with an IL-15/IL-15Ra superagonist complex, Ly-49 CD8 Tregs expanded robustly and became activated to suppress the Ag-specific Ab response. IL-15/IL-15Ra superagonist complex-activated CD8CD122 T cells also delayed diabetes transfer, indicating the presence of an underactivated CD8 T cell subset with regulatory capacity against late stage T1D. We identify a new cellular contribution to anti-islet autoimmunity and demonstrate the correction of this regulatory cell deficit. Infusion of IL-15-activated CD8 Tregs may serve as an innovative cellular therapy for the treatment of T1D.
Copyright © 2019 by The American Association of Immunologists, Inc.
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15 MeSH Terms
Widespread Tau-Specific CD4 T Cell Reactivity in the General Population.
Lindestam Arlehamn CS, Pham J, Alcalay RN, Frazier A, Shorr E, Carpenter C, Sidney J, Dhanwani R, Agin-Liebes J, Garretti F, Amara AW, Standaert DG, Phillips EJ, Mallal SA, Peters B, Sulzer D, Sette A
(2019) J Immunol 203: 84-92
MeSH Terms: Adult, Aged, Aged, 80 and over, Autoimmunity, CD4-Positive T-Lymphocytes, Cells, Cultured, Clonal Selection, Antigen-Mediated, Female, Humans, Immune Tolerance, Male, Middle Aged, Peptides, Phosphorylation, Protein Aggregation, Pathological, T-Cell Antigen Receptor Specificity, Young Adult, tau Proteins
Show Abstract · Added March 30, 2020
Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau-derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4 T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.
Copyright © 2019 by The American Association of Immunologists, Inc.
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1 Members
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MeSH Terms
Influenza Virus-Specific Human Antibody Repertoire Studies.
Crowe JE
(2019) J Immunol 202: 368-373
MeSH Terms: Antibodies, Viral, Antibody Diversity, Antigenic Variation, Antigens, Viral, B-Lymphocytes, Humans, Influenza A virus, Influenza Vaccines, Influenza, Human, Receptors, Antigen, B-Cell
Show Abstract · Added March 31, 2019
The diversity of Ag-specific adaptive receptors on the surface of B cells and in the population of secreted Abs is enormous, but increasingly, we are acquiring the technical capability to interrogate Ab repertoires in great detail. These Ab technologies have been especially pointed at understanding the complex issues of immunity to infection and disease caused by influenza virus, one of the most common and vexing medical problems in man. Influenza immunity is particularly interesting as a model system because the antigenic diversity of influenza strains and proteins is high and constantly evolving. Discovery of canonical features in the subset of the influenza repertoire response that is broadly reactive for diverse influenza strains has spurred the recent optimism for creating universal influenza vaccines. Using new technologies for sequencing Ab repertoires at great depth is helping us to understand the central features of influenza immunity.
Copyright © 2019 by The American Association of Immunologists, Inc.
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10 MeSH Terms
Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality.
Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL
(2018) J Immunol 201: 2873-2878
MeSH Terms: Animals, Animals, Newborn, Female, Humans, Infant, Newborn, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-1 Type I, Sepsis, Signal Transduction
Show Abstract · Added October 12, 2018
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
Copyright © 2018 by The American Association of Immunologists, Inc.
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2 Members
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14 MeSH Terms
How Superantigens Bind MHC.
Van Kaer L
(2018) J Immunol 201: 1817-1818
MeSH Terms: Animals, Antigens, Bacterial, Clonal Deletion, Enterotoxins, Histocompatibility Antigens, Humans, Lymphocyte Activation, Minor Lymphocyte Stimulatory Antigens, Peptide Fragments, Protein Binding, Receptors, Antigen, T-Cell, alpha-beta, Superantigens, T-Lymphocytes
Added March 26, 2019
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13 MeSH Terms
Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
1 Members
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17 MeSH Terms
Innate Immunity to : Evolving Paradigms in Soft Tissue and Invasive Infections.
Brandt SL, Putnam NE, Cassat JE, Serezani CH
(2018) J Immunol 200: 3871-3880
MeSH Terms: Animals, Bone and Bones, Humans, Immunity, Innate, Skin, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added March 18, 2020
causes a wide range of diseases that together embody a significant public health burden. Aided by metabolic flexibility and a large virulence repertoire, has the remarkable ability to hematogenously disseminate and infect various tissues, including skin, lung, heart, and bone, among others. The hallmark lesions of invasive staphylococcal infections, abscesses, simultaneously denote the powerful innate immune responses to tissue invasion as well as the ability of staphylococci to persist within these lesions. In this article, we review the innate immune responses to during infection of skin and bone, which serve as paradigms for soft tissue and bone disease, respectively.
Copyright © 2018 by The American Association of Immunologists, Inc.
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2 Members
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MeSH Terms
Links between Immunologic Memory and Metabolic Cycling.
Cottam MA, Itani HA, Beasley AA, Hasty AH
(2018) J Immunol 200: 3681-3689
MeSH Terms: Adaptive Immunity, Animals, Body Weight, Humans, Hypertension, Immunity, Innate, Immunologic Memory, Metabolic Diseases
Show Abstract · Added March 26, 2019
Treatments for metabolic diseases, such as diet and therapeutics, often provide short-term therapy for metabolic stressors, but relapse is common. Repeated bouts of exposure to, and relief from, metabolic stimuli results in a phenomenon we call "metabolic cycling." Recent human and rodent data suggest metabolic cycling promotes an exaggerated response and ultimately worsened metabolic health. This is particularly evident with cycling of body weight and hypertension. The innate and adaptive immune systems have a profound impact on development of metabolic disease, and current data suggest that immunologic memory may partially explain this association, especially in the context of metabolic cycling. In this Brief Review, we highlight recent work in this field and discuss potential immunologic mechanisms for worsened disease prognosis in individuals who experience metabolic cycling.
Copyright © 2018 by The American Association of Immunologists, Inc.
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8 MeSH Terms