A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCA) found an association between proteinase-3 (PR3) ANCA and a single-nucleotide polymorphism (SNP) (rs62132293) upstream of PRTN3, encoding PR3. The variant (G-allele) was shown to be an eQTL in healthy controls, but the clinical impact remains unknown. Longitudinally followed ANCA patients(n=401) and healthy controls(n=130) were genotyped. Gene expression was quantified by RT-qPCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Kaplan-Meier estimates and log rank test were used for clinical outcomes. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared to non-carriers (C/G vs. C/C and G/G vs. C/C, p=0.012 and p=0.001, respectively, effect size 0.24). Healthy controls had low PRTN3 regardless of genotype. MPO expression did not differ by genotype. PRTN3 (message) correlated with circulating PR3 (r=0.36, p<0.0005) and variant carriers had higher plasma PR3 compared to non-carriers (p=0.041). Among variant carriers, there was a 1.66-fold increased risk of relapse in patients with PR3-ANCA vs MPO-ANCA (HR 1.66, 95% CI 1.08, 2.54). The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.
Dhruti P. Chen, Claudia P. Aiello, DeMoris A. McCoy, Taylor Stamey, Jiajin Yang, Susan L. Hogan, Yichun Hu, Vimal K. Derebail, Eveline Y. Wu, J. Charles Jennette, Ronald J. Falk, Dominic J. Ciavatta
Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated novel mouse models with a 30-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared to controls with normal nephron number. Mice with low nephron number have reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.
Pamela I. Good, Ling Li, Holly A. Hurst, Ileana M. Serrano-Herrera, Katherine Xu, Meenakshi Rao, David A. Bateman, Qais Al-Awqati, Vivette D. D'Agati, Franklin Costantini, Fangming Lin
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of SREBP (sterol regulatory element binding protein) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immuno-metabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in Broncho Alveolar Lavage (BAL) cells isolated from IPF patients compared to healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 Peptide Nucleic Acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. Together, these studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a novel therapeutic approach to treat this disease.
Farida Ahangari, Nathan L. Price, Shipra Malik, Maurizio Chioccioli, Thomas Bärnthaler, Taylor S. Adams, Jooyoung Kim, Sai Pallavi Pradeep, Shuizi Ding, Carlos Cosme Jr, Kadi-Ann S. Rose, John E. McDonough, Nachelle R. Aurelien, Gabriel Ibarra, Norihito Omote, Jonas C. Schupp, Giuseppe DeIuliis, Julian A. Villalba Nunez, Lokesh Sharma, Changwan Ryu, Charles S. Dela Cruz, Xinran Liu, Antje Prasse, Ivan Rosas, Raman Bahal, Carlos Fernandez-Hernando, Naftali Kaminski
Activin receptor-like kinase 7 (ALK7) is a type I receptor in the transforming growth factor-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist-to-hip ratios and resistance to development of diabetes. The present study found that treatment with a neutralizing monoclonal antibody against ALK7 causes a substantial loss (40-60%) of adipose mass and improves glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and O2 consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term antibody treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and subsequently interleukin-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
Min Zhao, Katsuhide Okunishi, Yun Bu, Osamu Kikuchi, Hao Wang, Tadahiro Kitamura, Tetsuro Izumi
Human papillomaviruses (HPVs), are DNA viruses, including ~450 types, classified into five genera (α-, β-, γ-, µ-, and 𝜈-HPV). The γ- and β-HPVs are present in low-copy numbers in healthy individuals, however, in patients with an inborn error of immunity, certain species of β-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either “typical” or “atypical”. Manifestations in typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to β-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, on RNA extracted from normal-appearing skin and wart samples of patients with typical EV, to explore the viral and human genetic determinants. In 26 patients, nine distinct biallelic mutations in TMC6 (5), TMC8 (1), and CIB1 (3), seven being previously unreported, were detected. Additionally, 20 different HPV species, including three α-, 16 β-, and one γ-HPVs, were detected, eight of which are being reported for the first time in EV patients (β-HPV-37, -47, -80, -151, -159, α-HPV-2, -57, and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.
Amir Hossein Saeidian, Leila Youssefian, Mahtab Naji, Hamidreza Mahmoudi, Samantha M. Barnada, Charles Y. Huang, Karim Naghipoor, Amir Hozhabrpour, Jason S. Park, Flavia Manzo Margiotta, Fatemeh Vahidnezhad, Zahra Saffarian, Kambiz Kamyab-Hesari, Mohammad Tolouei, Niloofar Faraji, Seyyede Zeinab Azimi, Ghazal Namdari, Parvin Mansouri, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Jouni Uitto, Hassan Vahidnezhad
The molecular mediators of cell death and inflammation in Alzheimer’s disease (AD) have yet to be fully elucidated. Caspase-8 is a critical regulator of several cell death and inflammatory pathways; however, its role in AD pathogenesis has not yet been examined in detail. In the absence of Caspase-8, mice are embryonic lethal due to excessive RIPK3-dependent necroptosis. Compound RIPK3 and Caspase-8 mutants rescue embryonic lethality, which we leveraged to examine the roles of these pathways in an amyloid beta (Aβ)-mediated mouse model of AD. We find that combined deletion of Caspase-8 and RIPK3, but not RIPK3 alone, leads to diminished Aβ deposition and microgliosis in the 5xFAD mouse model of AD. Despite its well-known role in cell death, Caspase-8 does not appear to impact cell loss in the 5xFAD model. In contrast, we found that Caspase-8 is a critical regulator of Aβ-driven inflammasome gene expression and IL-1β release. Interestingly, loss of RIPK3 had only a modest effect on disease progression suggesting that inhibition of necroptosis or RIPK3-mediated cytokine pathways are not critical during mid stages of Aβ amyloidosis. These findings suggest that therapeutics targeting Caspase-8 may represent a novel strategy to limit Aꞵ amyloidosis and neuroinflammation in AD.
Sushanth Kumar, Sakar Budhathoki, Christopher B. Oliveira, August D. Kahle, O. Yipkin Calhan, John R. Lukens, Christopher D. Deppmann
Cystic fibrosis (CF) is characterized by chronic bacterial infections leading to progressive bronchiectasis and respiratory failure. Pseudomonas aeruginosa (Pa) is the predominant opportunistic pathogen infecting the CF airways. The guanine nucleotide exchange factor Vav3 plays a critical role in Pa adhesion to the CF airways by inducing luminal fibronectin deposition that favors bacteria trapping. Here we report that Vav3 overexpression in CF is caused by upregulation of the mRNA-stabilizing protein HuR. We found that HuR accumulates in the cytoplasm of CF airway epithelial cells, binds to and stabilizes Vav3 mRNA. Interestingly, disruption of HuR-Vav3 mRNA interaction improved the CF epithelial integrity, inhibited the formation of the fibronectin-made bacterial docking platforms and prevented Pa adhesion to the CF airway epithelium. These findings indicate that targeting HuR represents a promising anti-adhesive approach in CF to prevent initial stages of Pa infection in a context of emergence of multidrug resistant pathogens.
Mehdi Badaoui, Cyril Sobolewski, Alexandre Luscher, Marc Bacchetta, Thilo Köhler, Christian van Delden, Michelangelo Foti, Marc Chanson
Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque’s fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis shows that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.
Sergiy Sukhanov, Yusuke Higashi, Tadashi Yoshida, Svitlana Danchuk, Mitzi Alfortish, Traci Goodchild, Amy Scarborough, Thomas E. Sharp III, James S. Jenkins, Daniel Garcia, Jan Ivey, Darla L. Tharp, Jeffrey D. Schumacher, Zach Rozenbaum, Jay K Kolls, Douglas K. Bowles, David Lefer, Patrice Delafontaine
HIV non-progression despite persistent viraemia is rare among antiretroviral therapy (ART)-naïve adults, but relatively common among ART-naïve children. Previous studies indicate that ART-naïve paediatric slow-progressors (PSPs) adopt immune evasion strategies similar to those described in the SIV natural hosts. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8+ T-cells immediately prior to ATI was the main predictor of slow progression during ATI (r=0.77, p=0.002). PD-1+ CD8+ T-cell frequency was also negatively correlated with CCR5 (r=-0.74, p=0.005) and HLA-DR (r=-0.63, p=0.02) expression on CD4+ T-cells and predicted stronger HIV-specific T-lymphocyte responses. In the CD8+ T-cell compartment of PSPs, we identified an enrichment of stem-like TCF-1+PD-1+ memory cells, whereas paediatric progressors and viraemic adults were populated with a terminally exhausted PD-1+CD39+ population. TCF-1+PD-1+ expression on CD8+ T-cells was associated with higher proliferative activity (r=0.41, p=0.03) and stronger Gag-specific effector functionality. These data prompt the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in early-ART-treated infants with a preserved and non-exhausted T-cell compartment.
Vinicius Adriano Vieira, Nicholas Lim, Alveera Singh, Ellen Leitman, Reena R. D'Souza, Emily Adland, Maximilian Muenchhoff, Julia Roider, Miguel Á. Marín Lopez, Julieta Carabelli, Jennifer Giandhari, Andreas Groll, Pieter Jooste, Julia G. Prado, Christina Thobakgale, Krista Dong, Photini Kiepiela, Andrew J. Prendergast, Gareth Tudor-Williams, John Frater, Bruce D. Walker, Thumbi Ndung'u, Veron Ramsuran, Alasdair Leslie, Henrik N. Kløverpris, Philip Goulder
Pathogenic SOX2 variants typically cause severe ocular defects within a SOX2-disorder spectrum that includes hypogonadotropic hypogonadism (HH). We examined exome sequencing data from a large, well-phenotyped cohort of patients (n=1453) with Idiopathic Hypogonadotropic Hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified eight IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 is highly expressed in the hypothalamus of adult mice and colocalizes with KISS1 expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increases the levels of human kisspeptin luciferase transcription (hKISS-luc), while SOX2 overexpression represses hKiss-luc transcription. Further, four of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH attesting to hypothalamic defects in the SOX2-disorder spectrum. Our study describes novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.
Jessica Cassin, Maria I. Stamou, Kimberly W. Keefe, Kaitlin Sung, Celine Bojo, Karen J. Tonsfeldt, Rebecca A. Rojas, Vanessa Ferreira Lopes, Lacey Plummer, Kathryn B. Salnikov, David L. Keefe Jr., Metin Ozata, Myron Genel, Neoklis A. Georgopoulos, Janet E. Hall, William F. Crowley Jr., Stephanie B. Seminara, Pamela L. Mellon, Ravikumar Balasubramanian
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