Inflammation
Abstract
STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell–dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ–induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or type III IFN receptor (IFNλR1), ameliorated lung disease and restored lymph node development in SAVI mice. Furthermore, deletion of IFNGR1, but not IFNAR1 or IFNλR1, corrected the ratio of effector to Tregs in SAVI mice and in mixed bone marrow chimeric mice. Finally, cultured SAVI mouse macrophages were hyperresponsive to IFN-γ, but not IFN-β, in terms of Cxcl9 upregulation and cell activation. These results demonstrate that IFNGR1 plays a major role in autoinflammation and immune dysregulation mediated by STING gain of function.
Authors
W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner
Abstract
Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa-induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with lipopolysaccharides of P. aeruginosa, and is responsible for P. aeruginosa-induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1-dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa-induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa-induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa-induced pneumonia.
Authors
Pei-Shan Sung, Yu-Chun Peng, Shao-Ping Yang, Cheng-Hsun Chiu, Shie-Liang Hsieh
Abstract
The blood-brain barrier is formed by capillary endothelial cells expressing Cx37, Cx40 and Cx43, and is joined by closely apposed astrocytes expressing Cx43 and Cx30. We investigated whether connexin-targeting peptides could limit barrier leakage triggered by LPS-induced systemic inflammation in mice. Intraperitoneal LPS increased endothelial and astrocytic Cx43 expression, elevated TNFα, IL1β, IFNγ and IL6 in plasma and IL6 in the brain, and induced barrier leakage recorded over 24h. Barrier leakage was largely prevented by global Cx43 knockdown and Cx43/Cx30 double-knockout in astrocytes, slightly diminished by endothelial Cx43 knockout and not protected by global Cx30 knockout. Intravenous administration of Gap27 or Tat-Gap19 just before LPS also prevented barrier leakage, and intravenous BAPTA-AM to chelate intracellular calcium was equally effective. Patch-clamp experiments demonstrated LPS-induced Cx43 hemichannel opening in endothelial cells, which was suppressed by Gap27, Gap19 and BAPTA. LPS additionally triggered astrogliosis that was prevented by intravenous Tat-Gap19 or BAPTA-AM. Cortically applied Tat-Gap19 or BAPTA-AM to primarily target astrocytes, also strongly diminished barrier leakage. In vivo dye uptake and in vitro patch-clamp showed Cx43 hemichannel opening in astrocytes that was induced by IL6 in a calcium-dependent manner. We conclude that targeting endothelial and astrocytic connexins is a powerful approach to limit barrier failure and astrogliosis.
Authors
Marijke De Bock, Maarten A.J. De Smet, Stijn Verwaerde, Hanane Tahiri, Steffi Schumacher, Valérie Van Haver, Katja Witschas, Christian Steinhäuser, Nathalie Rouach, Roosmarijn E. Vandenbroucke, Luc Leybaert
Abstract
Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.
Authors
Carmelo Carmona-Rivera, Yu Zhang, Kerry Dobbs, Tovah E. Markowitz, Clifton L. Dalgard, Andrew J. Oler, Dillon R. Claybaugh, Deborah Draper, Meng Truong, Ottavia M. Delmonte, Francesco Licciardi, Ugo Ramenghi, Nicoletta Crescenzio, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Chiara Fiorini, Valentina Discepolo, Andrea Lo Vecchio, Alfredo Guarino, Luca Pierri, Andrea Catzola, Andrea Biondi, Paolo Bonfanti, Maria Cecilia Poli Harlowe, Yazmin Espinosa, Camila A. Astudillo, Emma Rey-Jurado, Cecilia Vial, Javiera De la Cruz, Ricardo Gonzalez, Cecilia Pinera, Jacqueline W. Mays, Ashley Ng, Andrew Platt, Beth A. Drolet, John Moon, Edward W. Cowen, Heather Kenney, Sarah E. Weber, Riccardo Castagnoli, Mary K. Magliocco, Michael Austin Stack, Gina A. Montealegre Sanchez, Karyl Barron, Danielle L. Fink, Douglas B. Kuhns, Stephen M. Hewitt, Lisa M. Arkin, Daniel S. Chertow, Helen C. Su, Luigi D. Notarangelo, Mariana J. Kaplan
Abstract
Psoriasis is a chronic, inflammatory skin disease, frequently associated with dyslipidemia. Lipid disturbance in psoriasis affects both circulatory system and cutaneous tissue. Epidermal Langerhans cells (LCs) are tissue-resident DCs that maintain skin immune surveillance and mediate various cutaneous disorders, including psoriasis. However, the role of LCs in psoriasis development and their lipid metabolic alternation remains unclear. Here, we demonstrate that epidermal LCs of psoriasis patients enlarge with longer dendrites and possess elevated IL-23p19 mRNA and a higher level of neutral lipids when compared with normal LCs of healthy individuals. Accordantly, epidermal LCs from imiquimod-induced psoriasis-like dermatitis in mice display overmaturation, enhanced phagocytosis, and excessive secretion of IL-23. Remarkably, these altered immune properties in lesional LCs are tightly correlated with elevated neutral lipid levels. Moreover, the increased lipid content of psoriatic LCs might result from impaired autophagy of lipids. Bulk RNA-Seq analysis identifies dysregulated genes involved in lipid metabolism, autophagy, and immunofunctions in murine LCs. Overall, our data suggest that dysregulated lipid metabolism influences LC immunofunction, which contributes to the development of psoriasis, and therapeutic manipulation of this metabolic process might provide an effective measurement for psoriasis.
Authors
Xilin Zhang, Xiaorui Li, Yuanyuan Wang, Youdong Chen, Yijun Hu, Chunyuan Guo, Zengyang Yu, Peng Xu, Yangfeng Ding, Qing-Sheng Mi, Jianhua Wu, Jun Gu, Yuling Shi
Abstract
α-1 antitrypsin (AAT) is a serine protease inhibitor that plays a pivotal role in maintaining lung homeostasis. The most common AAT allele associated with AAT deficiency (AATD) is PiZ. Z-AAT accumulates in cells due to misfolding, causing severe AATD. The major function of AAT is to neutralize neutrophil elastase in the lung. It is generally accepted that loss of antiprotease function is a major cause of COPD in individuals with AATD. However, it is now being recognized that the toxic gain-of-function effect of Z-AAT in macrophage likely contributes to lung disease. In the present study, we determined that TLR7 signaling is activated in Z-MDMs, and the expression level of NLRP3, one of the targets of TLR7 signaling, is significantly higher in Z- compared with M-MDMs. We also determined that the level of endosomal Alu RNA is significantly higher in Z-compared with M-MDMs. Alu RNA is a known endogenous ligand that activates TLR7 signaling. Z-AAT likely induces the expression of Alu elements in MDMs and accelerates monocyte death, leading to the higher level of endosomal Alu RNA in Z-MDMs. Taken together,this study identifies a mechanism responsible for the toxic gain of function of Z-AAT macrophages.
Authors
Jungnam Lee, Naweed Mohammad, Yuanqing Lu, Keunsoo Kang, Kyudong Han, Mark Brantly
Abstract
Liver diseases have become a major comorbidity health concern in people living with HIV-1 (PLWH) under combination antiretroviral therapy (cART). To investigate if HIV-1 infection and cART interact to lead to liver diseases, humanized mice reconstituted with progenitor cells from human fetal livers were infected with HIV-1 and treated with cART. We report here that chronic HIV-1 infection with cART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LM), elevated TGFβ and interferon signaling in the liver. Interestingly, IFN-I and TGFβ cooperatively activated human hepatic stellate cells (HepSC) in vitro. Mechanistically, IFN-I enhanced TGFβ-induced SMAD2/3 activation in HepSC. Finally, blockade of IFN-I signaling reversed HIV/cART-induced liver diseases in humanized mice. Consistent with the findings in humanized mice with HIV-1 and cART, we detected elevated markers of liver injury, M2-like macrophages, and of interferon signaling in blood specimens from PLWH over healthy individuals. These findings identify the IFN-I/M2LM/HepSC axis in HIV/cART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV/cART-associated liver diseases in PLWH under ART.
Authors
James Ahodantin, Kouki Nio, Masaya Funaki, Xuguang Zhai, Eleanor Wilson, Shyamasundaran Kottilil, Liang Cheng, Guangming Li, Lishan Su
Abstract
We describe a new mechanism responsible for Systemic Lupus Erythematosus (SLE). In humans with SLE and in two SLE murine models, there is marked enrichment of isolevuglandin (isoLG)-adducted proteins in monocytes and dendritic cells (DCs). We found that antibodies form against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduces transcription of all C1q subunits. Treatment of SLE prone mice with the specific isoLG scavenger 2-hydroxybenzlyamine (2HOBA) ameliorates parameters of autoimmunity including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowers blood pressure, attenuates renal injury, and reduces inflammatory gene expression uniquely in C1q expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
Authors
David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison
Abstract
Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single cell RNA sequencing of airway epithelium and mouse modeling, we find that IL-13 expands and programs airway tuft cells towards eicosanoid metabolism, and that tuft cell deficiency leads to a reduction in airway prostaglandin E2 (PGE2)concentration. Allergic airway epithelia bear a signature of prostaglandin E2 activation, and PGE2 activation leads to CFTR-dependent ion and fluid secretion and accelerated mucociliary transport. Together these data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
Authors
Maya E Kotas, Camille M. Moore, Jose G. Gurrola II, Steven D. Pletcher, Andrew N. Goldberg, Raquel Alvarez, Sheyla Yamato, Preston E. Bratcher, Ciaran A. Shaughnessy, Pamela L. Zeitlin, Irene H Zhang, Yingchun Li, Michael T. Montgomery, Keehoon Lee, Emily K. Cope, Richard M. Locksley, Max A. Seibold, Erin D. Gordon
Abstract
Preterm infants are susceptible to bloodstream infection by coagulase-negative staphylococci (CONS) that can lead to sepsis. High parenteral glucose supplement is commonly used to support their growth and energy expenditure, but may exceed endogenous regulation during infection, causing dysregulated immune response and clinical deterioration. Using a preterm piglet model of neonatal CONS sepsis induced by Staphylococcus epidermidis infection, we demonstrate the delicate interplay between immunity and glucose metabolism to regulate the host infection response. Circulating glucose levels, glycolysis and inflammatory response to infection are closely connected across the states of tolerance, resistance and immunoparalysis. Further, high parenteral glucose provision during infection induces hyperglycemia, elevated glycolysis and inflammation, leading to metabolic acidosis and sepsis, whereas glucose restricted individuals are clinically unaffected with increased gluconeogenesis to maintain moderate hypoglycemia. Finally, standard glucose supply maintaining normoglycemia or pharmacological glycolysis inhibition enhances bacterial clearance and dampens inflammation but fails to prevent sepsis. Our results uncover how blood glucose and glycolysis controls circulating immune responses, in turn determining the clinical fate of CONS infected preterm individuals. This questions the current practice of parenteral glucose supply for preterm infants during infection.
Authors
Tik Muk, Anders Brunse, Nicole L. Henriksen, Karoline Aasmul-Olsen, Duc Ninh Nguyen
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