Inflammatory bowel disease (IBD) is a chronic illness characterized by dysregulated immune cascades in the intestines, in which the Th17 immune response plays an important role. We demonstrated that mice with intestinal epithelium–specific deletion of Krüppel-like factor 5 (Klf5) developed Th17-dependent colonic inflammation. In the absence of KLF5, there was aberrant cellular localization of phosphorylated STAT3, an essential mediator of the Th17-associated cytokine, IL-22, which is required for epithelial tissue regeneration. In contrast, mitigation of IL-17A with anti–IL-17A neutralizing antibody attenuated colitis in Klf5-deficient mice. There was also a considerable shift in the colonic microbiota of Klf5-deficient mice that phenocopied human IBD. Notably, the inflammatory response due to Klf5 deletion was alleviated by antibiotic treatment, implicating the role of microbiota in pathogenesis. Finally, human colitic tissues had reduced KLF5 levels when compared with healthy tissues. Together, these findings demonstrated the importance of KLF5 in protecting the intestinal epithelium against Th17-mediated immune and inflammatory responses. The mice described herein may serve as a potential model for human IBD.
Jason Shieh, Timothy H. Chu, Yang Liu, Julie Kim, Ainara Ruiz de Sabando, Soma Kobayashi, Sui Y. Zee, Brian S. Sheridan, Agnieszka B. Bialkowska, Vincent W. Yang
Mutation of the TET2 DNA-hydroxymethylase has been associated with a number of immune pathologies. The disparity in phenotype and clinical presentation among these pathologies leads to questions regarding the role of TET2 mutation in promoting disease evolution in different immune cell types. Here we show that, in primary mast cells, Tet2 expression is induced in response to chronic and acute activation signals. In TET2-deficient mast cells, chronic activation via the oncogenic KITD816V allele associated with mastocytosis, selects for a specific epigenetic signature characterized by hypermethylated DNA regions (HMR) at immune response genes. H3K27ac and transcription factor binding is consistent with priming or more open chromatin at both HMR and non-HMR in proximity to immune genes in these cells, and this signature coincides with increased pathological inflammation signals. HMR are also associated with a subset of immune genes that are direct targets of TET2 and repressed in TET2-deficient cells. Repression of these genes results in immune tolerance to acute stimulation that can be rescued with vitamin C treatment or reiterated with a Tet inhibitor. Overall, our data support a model where TET2 plays a direct role in preventing immune tolerance in chronically activated mast cells, supporting TET2 as a viable target to reprogram the innate immune response for innovative therapies.
Riccardo Rigo, Rabie Chelbi, Julie Agopian, Sebastien Letard, Aurélien Griffon, Hussein Ghamlouch, Julien Vernerey, Vasileios Ladopoulos, Edwige Voisset, Paulo De Sepulveda, Geoffrey Guittard, Jacques A. Nunès, Ghislain Bidaut, Berthold Göttgens, Michael Weber, Olivier A. Bernard, Patrice Dubreuil, Erinn Soucie
Wound repair following acute injury requires a coordinated inflammatory response. Type I interferon (IFN) signaling is important for regulating the inflammatory response post- skin injury. IFN kappa (IFNκ), a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFNκ in the context of normal or dysregulated wound healing is unclear. Here, we found that Infκ expression is upregulated in keratinocytes early post-injury and is essential for normal tissue repair. Under diabetic conditions, IFNκ was decreased in wound keratinocytes, and early inflammation was impaired. Further, we found that the histone methyltransferase MLL1 is upregulated early following injury and regulates Infκ expression in diabetic wound keratinocytes via an H3K4me3 mediated mechanism. Using a series of in vivo studies with a genetically engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Infκ and MLL1 is decreased in T2D keratinocytes. Importantly, we find the administration of IFNκ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and re-epithelialization. These findings have significant implications for understanding the complex role type I interferons play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest IFNκ may be a viable therapeutic target to improve diabetic wound repair.
Sonya J. Wolf, Christopher O. Audu, Amrita Joshi, Aaron D. denDekker, William J. Melvin, Frank M. Davis, Xianying Xing, Rachael Wasikowski, Lam Tsoi, Steven Kunkel, Johann E. Gudjonsson, Mary X. O'Riordan, J. Michelle Kahlenberg, Katherine A. Gallagher
Identifying predictive biomarkers at early stages of early inflammatory arthritis is crucial for starting appropriate therapies to avoid poor outcomes. Monocytes and macrophages, largely associated with arthritis, are contributors and sensors of inflammation through epigenetic modifications. In this study, we investigated associations between clinical features and DNA methylation in blood and synovial fluid (SF) monocytes in a prospective cohort of early inflammatory arthritis patients. Undifferentiated arthritis (UA) blood monocyte DNA methylation profiles exhibited significant alterations in comparison with those from healthy donors. We identified additional differences both in blood and SF monocytes after comparing UA patients grouped by their future outcomes, good versus poor. Patient profiles in subsequent visits revealed a reversion towards a healthy level in both groups, those requiring disease-modifying antirheumatic drugs (DMARDs) and those that remitted spontaneously. Changes in disease activity between visits also impacted DNA methylation, partially concomitant in the SF of UA and in blood monocytes of rheumatoid arthritis patients. Epigenetic similarities between arthritis types allow a common prediction of disease activity. Our results constitute a resource of DNA methylation-based biomarkers of poor prognosis, disease activity and treatment efficacy in early untreated UA patients for the personalized clinical management of early inflammatory arthritis patients.
Carlos de la Calle-Fabregat, Javier Rodríguez-Ubreva, Laura Ciudad, Julio Ramírez, Raquel Celis, Ana B. Azuaga, Andrea Cuervo, Eduard Graell, Carolina Pérez-García, César Díaz-Torné, Georgina Salvador, José A. Gómez-Puerta, Isabel Haro, Raimon Sanmartí, Juan D. Cañete, Esteban Ballestar
The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges. During TLR ligand–mediated allergic sensitization, mice displayed transient airway neutrophilia, which triggered the release of TGF-β into the airway. This neutrophil-dependent production of TGF-β during sensitization had a delayed, suppressive effect on eosinophilic responses to subsequent allergen challenge. Neutrophil depletion during sensitization did not affect numbers of Foxp3+ Tregs but increased proportions of Gata3+CD4+ T cells, which, upon their transfer to recipient mice, triggered stronger eosinophilic inflammation. Thus, a neutrophil/TGF-β axis acts during TLR-mediated allergic sensitization to fine-tune the phenotype of developing allergen-specific CD4+ T cells and limit their pathogenicity, suggesting a novel immunotherapeutic approach to control eosinophilia in asthma.
Gregory S. Whitehead, Seddon Y. Thomas, Keiko Nakano, Derek J. Royer, Catherine G. Burke, Hideki Nakano, Donald N. Cook
Mechanisms governing entry and exit of immune cells into, and out of, inflamed joints, remain poorly understood. We sought herein to identify the key molecular pathways regulating such migration. Using murine models of inflammation in conjunction with mice expressing a photoconvertible fluorescent protein we characterized the migration of cells from joints to draining lymph nodes (LN) and performed RNA-seq analysis on isolated cells, identifying genes associated with migration and retention. We further refined the gene list to those specific for joint inflammation. RNA-seq data revealed pathways and genes previously highlighted as characteristic of RA in patient studies, validating the methodology. Focusing on gene regulatory pathways associated with cell migration, adhesion and movement, we identified genes involved in the retention of immune cells in the inflamed joint, namely JAM-A, and identified a role for such molecules in T cell differentiation in vivo.Thus, using a combination of novel cell tracking approaches and murine models of inflammatory arthritis we have identified genes, pathways and anatomically specific tissue signatures regulating cell migration in a variety of inflamed sites. This unique skin and joint specific dataset will be an invaluable resource for the identification of novel therapeutic targets for arthritis and other inflammatory disorders.
Catriona T. Prendergast, Robert A. Benson, Hannah E. Scales, Caio S. Bonilha, John J. Cole, Iain McInnes, James M. Brewer, Paul Garside
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
Catharina Conrad, Daniela Yildiz, Simon J. Cleary, Andreas Margraf, Lena Cook, Uwe Schlomann, Barry Panaretou, Jessica L. Bowser, Harry Karmouty-Quintana, Jiwen Li, Nathaniel K. Berg, Samuel C. Martin, Ahmad Aljohmani, S. Farshid Moussavi-Harami, Kristin M. Wang, Jennifer J. Tian, Mélia Magnen, Colin Valet, Longhui Qiu, Jonathan P. Singer, Holger K. Eltzschig, CAPSys Study Group, Wilhelm Bertrams, Susanne Herold, Norbert Suttorp, Bernd Schmeck, Zachary T. Ball, Alexander Zarbock, Mark R. Looney, Jörg W. Bartsch
Following myocardial infarction (MI), elderly patients have a poorer prognosis which may belinked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), anewly discovered pro-inflammatory member of the IL-1 superfamily, may mediate this injurybut its role in the injured heart is currently not known. We firstly demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischaemia-reperfusion (IR) injured mouse hearts and,interestingly, noted that expression of both increased with ageing. An intravital modelfor imaging the adult and aged IR injured beating heart in real-time in vivo was used todemonstrate heightened basal and injury-induced neutrophil recruitment, and poorer bloodflow, in the aged coronary microcirculation when compared to adult hearts. An IL-36Rantagonist (IL-36Ra) significantly decreased neutrophil recruitment, improved blood flow andreduced infarct size in both adult and aged mice. This may be mechanistically explained byattenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra treated mice.Our findings of an enhanced age-related coronary microcirculatory dysfunction inreperfused hearts may explain the poorer outcomes in elderly patients following MI. Sincetargeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly.
Juma El-Awaisi, Dean P.J. Kavanagh, Marco R. Rink, Chris J. Weston, Nigel E. Drury, Neena Kalia
Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A2 (sPLA2-IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA2-IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA2-IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota. Metagenome, transcriptome, and metabolome analyses have revealed that sPLA2-IIA deficiency alters the gut microbiota, accompanied by notable changes in the intestinal expression of genes related to immunity and metabolism, as well as in the levels of various blood metabolites and fecal bacterial lipids, suggesting that sPLA2-IIA contributes to shaping of the gut microbiota. The skin phenotypes in Pla2g2a–/– mice are lost (a) when they are cohoused with littermate WT mice, resulting in the mixing of the microbiota between the genotypes, or (b) when they are housed in a more stringent pathogen-free facility, where Pla2g2a expression in WT mice is low and the gut microbial compositions in both genotypes are nearly identical. Thus, our results highlight a potentially new aspect of sPLA2-IIA as a modulator of gut microbiota, perturbation of which affects distal skin responses.
Yoshimi Miki, Yoshitaka Taketomi, Yuh Kidoguchi, Kei Yamamoto, Kazuaki Muramatsu, Yasumasa Nishito, Jonguk Park, Koji Hosomi, Kenji Mizuguchi, Jun Kunisawa, Tomoyoshi Soga, Eric Boilard, Siddabasave Gowda B. Gowda, Kazutaka Ikeda, Makoto Arita, Makoto Murakami
Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.
Etienne Doré, Charles Joly-Beauparlant, Satoshi Morozumi, Alban Mathieu, Tania Lévesque, Isabelle Allaeys, Anne-Claire Duchez, Nathalie Cloutier, Mickaël Leclercq, Antoine Bodein, Christine Payré, Cyril Martin, Agnes Petit-Paitel, Michael H. Gelb, Manu Rangachari, Makoto Murakami, Laetitia Davidovic, Nicolas Flamand, Makoto Arita, Gérard Lambeau, Arnaud Droit, Eric Boilard
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