HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA–forming microsatellite

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 3039-3048 ◽  
Author(s):  
Henry K. Bayele ◽  
Carole Peyssonnaux ◽  
Alexandra Giatromanolaki ◽  
Wagner W. Arrais-Silva ◽  
Hiba S. Mohamed ◽  
...  
Keyword(s):  
Disease Risk ◽  
Allelic Variation ◽  
Inflammatory Diseases ◽  
Inbred Mice ◽  
Hypoxia Inducible Factor ◽  
Immune Response Gene ◽  
Allelic Association ◽  
Heritable Variation ◽  
Allele Expression ◽  
Z Dna

AbstractThe Ity/Lsh/Bcg locus encodes the macrophage protein Slc11a1/Nramp1, which protects inbred mice against infection by diverse intracellular pathogens including Leishmania, Mycobacterium, and Salmonella. Human susceptibility to infectious and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and tuberculosis, shows allelic association with a highly polymorphic regulatory, Z-DNA–forming microsatellite of (GT/AC)n dinucleotides within the proximal SLC11A1 promoter. We surmised that cis-acting allelic polymorphisms may underlie heritable differences in SLC11A1 expression and phenotypic variation in disease risk. However, it is unclear what may underlie such variation in SLC11A1 allele expression. Here we show that hypoxia-inducible Factor 1 (HIF-1) regulates allelic variation in SLC11A1 expression by binding directly to the microsatellite during macrophage activation by infection or inflammation. Targeted Hif-1α ablation in murine macrophages attenuated Slc11a11 expression and responsiveness to S typhimurium infection. Our data also showed that HIF-1 may be functionally linked to complex prototypical inflammatory diseases associated with certain SLC11A1 alleles. As these alleles are highly polymorphic, our finding suggests that HIF-1 may influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation within and between populations. This report also suggests that microsatellites may play critical roles in the directional evolution of complex heritable traits by regulating gene expression phenotypes.

scholarly journals APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

2019 ◽  
Vol 316 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Leslie A. Bruggeman ◽  
John F. O’Toole ◽  
John R. Sedor
Keyword(s):  
Kidney Disease ◽  
Human Genetics ◽  
Disease Risk ◽  
Kidney Diseases ◽  
Expression Patterns ◽  
Model Systems ◽  
Recessive Trait ◽  
Loss Of Function ◽  
Allele Expression ◽  
Basic Biology

The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

scholarly journals Individualized VDJ recombination predisposes the available Ig sequence space

2021 ◽  
Author(s):  
Andrei Slabodkin ◽  
Maria Chernigovskaya ◽  
Ivana Mikocziova ◽  
Rahmad Akbar ◽  
Lonneke Scheffer ◽  
...  
Keyword(s):  
Sequence Space ◽  
Distance Measure ◽  
Allelic Variation ◽  
Inbred Mice ◽  
Individualized Medicine ◽  
Monozygotic Twins ◽  
Antigen Recognition ◽  
Sequencing Data ◽  
Vdj Recombination ◽  
Individual Comparison

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire, and consequently (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual-specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also non-genetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

scholarly journals Determinants of hypoxia-inducible factor activity in the intestinal mucosa

2017 ◽  
Vol 123 (5) ◽  
pp. 1328-1334 ◽  
Author(s):  
Raphael R. Fagundes ◽  
Cormac T. Taylor
Keyword(s):  
Intestinal Mucosa ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Oxygen Demand ◽  
Intestinal Lumen ◽  
Adaptation To Hypoxia ◽  
Healthy Mucosa ◽  
Microenvironmental Factors ◽  
Anoxic Environment

The intestinal mucosa is exposed to fluctuations in oxygen levels due to constantly changing rates of oxygen demand and supply and its juxtaposition with the anoxic environment of the intestinal lumen. This frequently results in a state of hypoxia in the healthy mucosa even in the physiologic state. Furthermore, pathophysiologic hypoxia (which is more severe and extensive) is associated with chronic inflammatory diseases including inflammatory bowel disease (IBD). The hypoxia-inducible factor (HIF), a ubiquitously expressed regulator of cellular adaptation to hypoxia, is central to both the adaptive and the inflammatory responses of cells of the intestinal mucosa in IBD patients. In this review, we discuss the microenvironmental factors which influence the level of HIF activity in healthy and inflamed intestinal mucosae and the consequences that increased HIF activity has for tissue function and disease progression.

scholarly journals HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3343-3354 ◽  
Author(s):  
Marzia Scortegagna ◽  
Christophe Cataisson ◽  
Rebecca J. Martin ◽  
Daniel J. Hicklin ◽  
Robert D. Schreiber ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cancer Metastasis ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Local Environment ◽  
Inflammatory Cells ◽  
Hypoxia Inducible Factor 1 ◽  
Inflammatory Protein ◽  
Multiple Cell ◽  
Epithelial Inflammation

AbstractHypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.

scholarly journals Modeling transfer of vaginal microbiota from mother to infant in early life

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Martin Steen Mortensen ◽  
Morten Arendt Rasmussen ◽  
Jakob Stokholm ◽  
Asker Daniel Brejnrod ◽  
Christina Balle ◽  
...  
Keyword(s):  
Early Life ◽  
Disease Risk ◽  
Inflammatory Diseases ◽  
Vaginal Microbiota ◽  
Delivery Mode ◽  
Vaginal Microbiome ◽  
Third Trimester ◽  
Chronic Inflammatory Diseases ◽  
The Third ◽  
Initial Seeding

Early-life microbiota has been linked to the development of chronic inflammatory diseases. It has been hypothesized that maternal vaginal microbiota is an important initial seeding source and therefore might have lifelong effects on disease risk. To understand maternal vaginal microbiota’s role in seeding the child’s microbiota and the extent of delivery mode-dependent transmission, we studied 665 mother–child dyads from the COPSAC2010 cohort. The maternal vaginal microbiota was evaluated twice in the third trimester and compared with the children’s fecal (at 1 week, 1 month, and 1 year of age) and airway microbiota (at 1 week, 1 month, and 3 months). Based on the concept of weighted transfer ratios (WTRs), we have identified bacterial orders for which the WTR displays patterns indicate persistent or transient transfer from the maternal vaginal microbiome, as well as orders that are shared at later time points independent of delivery mode, indicating a common reservoir.

scholarly journals Correlation study between Interleukin-17 Gene Polymorphisms and risk of development of recurrent aphthous ulcer in Han Chinese Population

2020 ◽  
Author(s):  
Haidong Xiang ◽  
Dongmei Cheng ◽  
Han Guo ◽  
Yan Wang ◽  
Zhiyu Jia ◽  
...  
Keyword(s):  
Chinese Population ◽  
Disease Risk ◽  
Inflammatory Diseases ◽  
Correlation Study ◽  
Aphthous Ulcer ◽  
Interleukin 17 ◽  
Genotype Distribution ◽  
Chain Reaction ◽  
Drinking Status ◽  
Polymerase Chain

Abstract Objective Interleukin-17 (IL-17) is a pleiotropic cytokine which plays important role in the inflammatory diseases.Methods: Polymorphisms of IL-17A rs2275913 and IL17F rs763780 were measured in 125 RAU cases and 116 healthy controls. The polymerase chain reaction-restriction fragment length was measured. The genotype distribution and disease risk, and its’ relationship with RAU severity was analyzed. Results: RAU risk were related with polymorphism of IL-17 gene at rs2275913 site after adjusting BMI, sex, age, smoking and drinking status (AA vs. GG: odds ratio (OR), 1.624; 95% confidence interval (CI), 1.125–2.250; P = 0.030; A allele vs. G allele: OR, 1.192; P = 0.037; 95% CI, 1.012–1.404;). In addition, the rs763780 variant genotypes (TC and CC) and C allele also have higher relevance to RAU compared with subjects who bears the TT genotype (TC vs. TT, OR: 1.312; P = 0.039; 95% CI: 1.017–1.692; CC vs. TT, OR: 2.812, P = 0.006, 95% CI: 1.338-5.909; C allele Vs. T allele, OR:1.413, P=0.002, 95% CI:1.141-1.751). We also found serum IL-17 levels were greatly higher in RAU patients compared with controls (P = 0.001), and serum IL17 concentration is correlated with IL17 polymorphism. Conclusion: Our research showed polymorphisms of IL-17 gene might related to the high-risk of RAU occurrence.

scholarly journals Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ruidong Li ◽  
Peng Zhang ◽  
Yaxin Wang ◽  
Kaixong Tao
Keyword(s):  
Immune Response ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Aerobic Glycolysis ◽  
Tricarboxylic Acid Cycle ◽  
Immune Response Gene ◽  
Related Factor ◽  
Therapeutic Implications ◽  
Inflammatory Status ◽  
Inflammatory Stimuli

Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process can be diverted to generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, the immune response gene 1 is activated and promotes the production of itaconate from the tricarboxylic acid cycle by decarboxylating cis-aconitate. Itaconate has been reported to have multiple immunoregulatory and antioxidative effects. In addition, reports have described its antibacterial and protumor effects. The involved mechanism in these effects includes the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, inhibition of aerobic glycolysis by targeting glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, inhibition of succinate dehydrogenase, and blockade of IκBζ translation. All of these discoveries elucidated the transformation of the pro- into anti-inflammatory status in macrophages, which is crucial in innate immunity and set the ground for the emerging therapeutic implications of itaconate. In this review, we point out that itaconate is a novel and pivotal metabolic determinant of the immunoregulatory response in macrophages and highlight studies that have improved our understanding of the connection between the immune response and metabolism. In addition, we shed light on the therapeutic potential of itaconate and its derivatives to treat inflammatory diseases.

scholarly journals Temporal variation in an immune response gene (MHC I) in anadromous Salmo trutta in an Irish river before and during aquaculture activities

2006 ◽  
Vol 63 (7) ◽  
pp. 1248-1255 ◽  
Author(s):  
James Coughlan ◽  
Philip McGinnity ◽  
Brian O'Farrell ◽  
Eileen Dillane ◽  
Ola Diserud ◽  
...  
Keyword(s):  
Immune Response ◽  
Salmo Trutta ◽  
Allelic Variation ◽  
Gene Diversity ◽  
Marker Locus ◽  
Immune Response Gene ◽  
Mhc I ◽  
Sea Trout ◽  
Salmon Aquaculture ◽  
Steep Decline

Abstract Several studies have documented the genetic effects of intraspecific hybridization of cultured and wild Atlantic salmon (Salmo salar L.). However, the effect of salmon aquaculture on wild congeners is not so well understood. Diseases, introduced or increased in incidence by salmon aquaculture activities, may have an impact on co-occurring wild sea trout (Salmo trutta L.), as implied by the steep decline in sea trout numbers in many Irish, Scottish, and Norwegian rivers since the late 1980s, which may be linked to sea lice infestations associated with marine salmonid farming. Our data suggest that salmon farming and ocean ranching can indirectly affect, most likely mediated by disease, the genetics of cohabiting sea trout by reducing variability at major histocompatibility class I genes. We studied samples of DNA extracted from scales of sea trout in the Burrishoole River, in the west of Ireland, before and at intervals during aquaculture activities. In these samples, allelic variation at a microsatellite marker, tightly linked to a locus critical to immune response (Satr-UBA), was compared with variation at six neutral microsatellite loci. A significant decline in allelic richness and gene diversity at the Satr-UBA marker locus, observed since aquaculture started and which may indicate a selective response, was not reflected by similar reductions at neutral loci. Subsequent recovery of variability at the Satr-UBA marker, seen among later samples, may reflect an increased contribution by resident brown trout to the remaining sea trout stock.

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