Nicolas Lapaque

Publications (20) View all

• Source

  Available from: Hans Janssen

  Dataset: Supplemental Data

  John Trowsdale, Yu Hui Kang, Adrian P Kelly, Hans Janssen, Nicolas Lapaque, Nicola P Jackson
• Article: ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilize independent pathways.

  Agata Korecka, Tomas de Wouters, Antonietta Cultrone, Nicolas Lapaque, Sven Pettersson, Joël Doré, Hervé M Blottière, Velmurugesan Arulampalam
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  ABSTRACT: Short chain fatty acids (SCFAs), such as butyrate and propionate, are metabolic products of carbohydrate fermentation by the microbiota and constitute the main source of energy for host colonocytes. SCFAs are also important for gastrointestinal health, immunity and host metabolism. Intestinally produced ANGPTL4 is a secreted protein with metabolism-altering properties and may offer a route by which microbiota can regulate host metabolism. PPARγ has previously been shown to be involved in microbiota-induced expression of intestinal ANGPTL4, but the role of bacterial metabolites in this process has remained elusive. Here, we show that the SCFA butyrate regulates intestinal ANGPTL4 expression in a PPARγ-independent manner. Although PPARγ is not required for butyrate-driven intestinal ANGPTL4 expression, co-stimulating with PPARγ ligands and SCFAs leads to additive increases in ANGPTL4 levels. We suggest that PPARγ and butyrate rely on two separate regulatory sites, a PPRE downstream the transcription start site and a butyrate responsive element(s) (BRE) within the promoter region, 0.5kb upstream of the transcription start site. Furthermore, butyrate gavage and colonization with C. tyrobutyricum, a SCFA producer, can independently induce expression of intestinal ANGPTL4 in germfree mice. Thus, oral administration of SCFA or use of SCFA-producing bacteria may be additional routes to maintain intestinal ANGPTL4 levels for preventive nutrition or therapeutic purposes.
  AJP Gastrointestinal and Liver Physiology 03/2013; · 3.43 Impact Factor
• Article: HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding.

  Des C Jones, Vasilis Kosmoliaptsis, Richard Apps, Nicolas Lapaque, Isobel Smith, Azumi Kono, Chiwen Chang, Louise H Boyle, Craig J Taylor, John Trowsdale, Rachel L Allen
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  ABSTRACT: Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded β(2)-microglobulin-associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.
  The Journal of Immunology 03/2011; 186(5):2990-7. · 5.79 Impact Factor
• Source

  Available from: Nicolas Lapaque

  Article: Anaesthetic impairment of immune function is mediated via GABA(A) receptors.

  Daniel W Wheeler, Andrew J Thompson, Federico Corletto, Jill Reckless, Justin C T Loke, Nicolas Lapaque, Andrew J Grant, Pietro Mastroeni, David J Grainger, Claire L Padgett, John A O'Brien, Nigel G A Miller, John Trowsdale, Sarah C R Lummis, David K Menon, John S Beech
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  ABSTRACT: GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients. We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.
  PLoS ONE 01/2011; 6(2):e17152. · 4.09 Impact Factor
• Article: HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding.

  Jones DC, Kosmoliaptsis V, Apps R, Lapaque N, Smith I, Kono A, Chang C, Boyle LH, Taylor CJ, Trowsdale J, Allen RL
  [show abstract] [hide abstract]
  ABSTRACT: Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease.We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded b2-microglobulin–associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.
  Journal of immunology. 01/2011; 186.