Inappropriate immune activity is key in the pathogenesis of multiple diseases and is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector due to its powerful role in both innate and adaptive immunity, and thus is tightly controlled at multiple levels. IL-1R2 antagonises IL-1, but effects of losing this regulation is unknown. We find IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal centre (GC) T follicular regulatory (Tfr) cells increases the GC response after a first, but not booster, immunisation, with more T follicular helper (Tfh) cells, GC B cells and antigen-specific antibodies, which is reversed upon IL-1 blockade. However, IL-1 signalling is not obligate for GC reactions, as wildtype and Il1r1–/– mice show equivalent phenotypes, suggesting GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2–/– mice do not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulates it, implying compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn’s disease have lower serum IL-1R2. Together, we show that IL-1R2 controls important aspects of innate and adaptive immunity, and that IL-1R2 level may contribute to human disease propensity and/or progression.
Katerina Pyrillou, Melanie Humphry, Lauren A. Kitt, Amanda Rodgers, Meritxell Nus, Martin R. Bennett, Kenneth G.C. Smith, Paul A. Lyons, Ziad Mallat, Murray C.H. Clarke
Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. AD patients are at heightened risk for Staphylococcus aureus (S. aureus) infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33f/fK14cre mice and Tlr2–/– mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.
Chia-Hui Luo, Alan Chuan-Ying Lai, Chun-Chou Tsai, Wei-Yu Chen, Yu-Shan Chang, Ethan Ja-Chen Chung, Ya-Jen Chang
Pattern-Recognition Receptor responses are profoundly attenuated before the third trimester of gestation, in the relatively low oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes, and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period, and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Together, these data show that DDIT4L regulates mitochondrial activity and provide the first direct evidence for its potential role regulating innate immune activity in myeloid cells during development.
Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie
Cauterization of the root of the left coronary artery (LCA) in the neonatal heart at postnatal day 1 (P1) resulted in large reproducible lesions of the left ventricle (LV), and an attendant marked adaptive response in the right ventricle (RV). The response of both chambers to LV myocardial infarction involved enhanced cardiomyocyte (CM) division and binucleation, as well as LV re-vascularization, leading to restored heart function within 7 days post-surgery (7 dps). By contrast, infarction of P3 mice resulted in cardiac scarring without a significant regenerative and adaptive response of the LV and the RV leading to subsequent heart failure and death within 7 dps. The prominent RV myocyte expansion in P1 mice involved an acute increase in pulmonary arterial pressure and a unique gene regulatory response, leading to an increase in RV mass and preserved heart function. Thus, distinct adaptive mechanisms in the RV, such as CM proliferation and RV expansion, enable marked cardiac regeneration of the infarcted LV at P1 and full functional recovery.
Tianyuan Hu, Mona Malek Mohammadi, Fabian Ebach, Michael Hesse, Michael I. Kotlikoff, Bernd K. Fleischmann
Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low- versus high-risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state whereas invasiveness genes were linked with Epgn3 high-risk status. We identified ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
Karen Mendelson, Tiphaine C. Martin, Christie B. Nguyen, Min Hsu, Jia Xu, Claudia C.V. Lang, Reinhard Dummer, Yvonne Saenger, Jane L. Messina, Vernon K. Sondak, Garrett Desman, Dan Hasson, Emily Bernstein, Ramon E. Parsons, Julide Tok Celebi
Acute bacterial orchitis (AO) is a prevalent cause of intra-scrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins (IRP) 1 and 2 and these factors are reported to play a role in testicular and immune cell function, however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in reduced immune response and testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infected Irp1–/– mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT and Irp2–/– mice, no increase in monocytes and neutrophils was detected in testis of Irp1–/– mice upon UPEC-infection. Interestingly, in Irp1–/– UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.
Niraj Ghatpande, Aileen Harrer, Bar Azoulay-Botzer, Noga Guttmann-Raviv, Sudhanshu Bhushan, Andreas Meinhardt, Esther G. Meyron-Holtz
Geleophysic Dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTSL2 variants. It is characterized by distinctive facial features, limited joint mobility, short stature with brachydactyly, and the potential for life-threatening cardiovascular and respiratory complications. The clinical spectrum spans from perinatal lethality to milder phenotypes in adult survivors, manifesting a clinical heterogeneity. The Adamtsl2–/– mouse model dies perinatally and hinders further functional investigation. In this study, we developed and characterized cellular and mouse models, which were designed to replicate the genetic profile of a patient who is compound heterozygous for two ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but notably, p.A165T exhibited a more severe impact. We conducted a thorough analysis of mice carrying different allelic combinations, including knockout, p.R61H, and p.A165T variants. This examination revealed a wide spectrum of phenotypic severity, spanning from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. While they survived, the homozygous and hemizygous p.A165T mice displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affects the expiration phase without significant fibrosis in the lungs. Evidence of microscopic post-obstructive pneumonia was found in some hemizygous and homozygous p.A165T. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction in the size of the aortic root. Histological examinations further confirmed the presence of hypertrophic cardiomyopathy with myocyte hypertrophy. In addition, evidence of elevated proteoglycan staining in the myocardium, chondroid metaplasia, along with patchy mild interstitial fibrosis within the myocardium was seen in hemizygous and homozygous p.A165T. In conclusion, our study revealed a significant correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1. The surviving mouse models we developed have provided valuable insights into the pathogenesis of GD and hold promise as valuable tools for informing and guiding future therapeutic interventions aimed at managing this disorder effectively.
Vladimir Camarena, Monique M. Williams, Alejo A. Morales, Mohammad F. Zafeer, Okan V. Kilic, Ali Kamiar, Clemer Abad, Monica A. Rasmussen, Laurence M. Briski, LéShon Peart, Guney Bademci, Deborah S. Barbouth, Sarah Smithson, Gaofeng Wang, Lina A. Shehadeh, Katherina Walz, Mustafa Tekin
TDP-43 is a DNA/RNA-binding protein that regulates gene expression and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its role in endothelial cells (ECs), angiogenesis and vascular function. Using inducible EC-specific TDP-43 knockout mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity and blood vessel stability. Postnatal EC-specific deletion of TDP-43 leaded to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the central-nervous system with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted fibronectin matrix around sprouting vessels and reduced -catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.
Víctor Arribas, Yara Onetti, Marina Ramiro-Pareta, Pilar Villacampa, Heike Beck, Mariona Alberola, Anna Esteve-Codina, Angelika Merkel, Markus Sperandio, Ofelia M. Martínez-Estrada, Bettina Schmid, Eloi Montanez
Adoptive transfer of immune regulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of non-relapse mortality after allogeneic hematopoietic stem-cell transplantation. Mucosal-associated invariant T cells (MAITs) were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAITs in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic-GVHD model. We found that MAIT cells, whether freshly purified or shortly expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAITs strongly delayed GVHD onset and severity when transferred early after PBMC injection, but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels, and increased IL-10 levels. MAITs acted partly in a contact-dependent manner, which likely required direct interaction of their TCR with MR1 induced on host-reactive T cells. These results support the setup of clinical trials using MAITs as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.
Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman
Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/−) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/− mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/− mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifts cell fate more toward the myeloid lineage but compromises lymphoid lineage development by reducing genes required for lymphoid and B-cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.
Lana Vukadin, Bohye Park, Mostafa Mohamed, Huashi Li, Amr Elkholy, Alex Torrelli-Diljohn, Jung-Hyun Kim, Kyuho Jeong, James M. Murphy, Caitlin A. Harvey, Sophia Dunlap, Leah Gehrs, Hanna Lee, Hyung-Gyoon Kim, Jay Prakash Sah, Seth N. Lee, Denise Stanford, Robert A. Barrington, Jeremy B. Foote, Anna G. Sorace, Robert S. Welner, Blake E. Hildreth III, Ssang-Taek Steve Lim, Eun-Young Erin Ahn
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