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      The role of integrin alpha v beta 8 on human monocytes and macrophages in intestinal immune homeostasis

      Shuttleworth, Elinor

      [Thesis]. Manchester, UK: The University of Manchester; 2018.

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      Abstract

      Intestinal immune cells remain tolerant to the trillions of commensal bacteria present in the gut, with perturbations of this process implicated in development of inflammatory bowel disease (IBD). The cytokine TGF-beta is a key factor promoting intestinal immune tolerance, but is secreted in a latent state that requires activation to function. Binding of TGF-beta to the integrin alpha v beta 8 is a principal mechanism of TGF-beta activation, with mouse models demonstrating a crucial role for alpha v beta 8 expression by dendritic cells and regulatory T cells in intestinal immune regulation. Despite this evidence, very little is known regarding the importance of this activating integrin in human intestinal homeostasis. Utilising flow cytometry here we find that integrin alpha v beta 8 is highly expressed on peripheral blood monocytes with highest levels on intermediate CD14++CD16+ monocytes. Upon monocyte to macrophage differentiation high beta 8 expression is observed on anti-inflammatory M-CSF differentiated macrophages versus pro-inflammatory GM-CSF macrophages. In monocytes, expression of beta 8 is upregulated by specific bacterial TLR ligands. Utilising a TGF-beta reporter cell line both monocytes and M-CSF MDM display an enhanced ability to activate TGF-beta in an alpha v beta 8-dependent manner. Data presented here indicate that macrophage alpha v beta 8-dependent TGF-beta activation does not alter expression of surface markers associated with a tolerogenic macrophage phenotype, phagocytosis, or production of the anti-inflammatory cytokine IL-10; nor does TGF-beta appear to influence the metabolic profile of macrophages, key differences of which are associated with pro- or anti-inflammatory phenotype. However, the previously undescribed finding of integrin alpha v beta 8 expression on human monocytes and macrophages, which was subsequently confirmed in intestinal populations and found to be downregulated in inflamed IBD mucosa, may highlight an important functional pathway in intestinal immune homeostasis and represent a potential future therapeutic target in IBD.

      Bibliographic metadata

      Type of resource:
      Content type:
      Administered thesis
      Form of thesis:
      Traditional
      Type of submission:
      Doctoral level ETD - final
      Thesis title:
      The role of integrin alpha v beta 8 on human monocytes and macrophages in intestinal immune homeostasis
      Degree type:
      Doctor of Philosophy
      Degree programme:
      PhD Immunology 3yr (IIRM)
      Publication date:
      2018-11-25T23:15:05
      Institution:
      The University of Manchester
      Location:
      Manchester, UK
      Total pages:
      189
      Abstract:
      Intestinal immune cells remain tolerant to the trillions of commensal bacteria present in the gut, with perturbations of this process implicated in development of inflammatory bowel disease (IBD). The cytokine TGF-beta is a key factor promoting intestinal immune tolerance, but is secreted in a latent state that requires activation to function. Binding of TGF-beta to the integrin alpha v beta 8 is a principal mechanism of TGF-beta activation, with mouse models demonstrating a crucial role for alpha v beta 8 expression by dendritic cells and regulatory T cells in intestinal immune regulation. Despite this evidence, very little is known regarding the importance of this activating integrin in human intestinal homeostasis. Utilising flow cytometry here we find that integrin alpha v beta 8 is highly expressed on peripheral blood monocytes with highest levels on intermediate CD14++CD16+ monocytes. Upon monocyte to macrophage differentiation high beta 8 expression is observed on anti-inflammatory M-CSF differentiated macrophages versus pro-inflammatory GM-CSF macrophages. In monocytes, expression of beta 8 is upregulated by specific bacterial TLR ligands. Utilising a TGF-beta reporter cell line both monocytes and M-CSF MDM display an enhanced ability to activate TGF-beta in an alpha v beta 8-dependent manner. Data presented here indicate that macrophage alpha v beta 8-dependent TGF-beta activation does not alter expression of surface markers associated with a tolerogenic macrophage phenotype, phagocytosis, or production of the anti-inflammatory cytokine IL-10; nor does TGF-beta appear to influence the metabolic profile of macrophages, key differences of which are associated with pro- or anti-inflammatory phenotype. However, the previously undescribed finding of integrin alpha v beta 8 expression on human monocytes and macrophages, which was subsequently confirmed in intestinal populations and found to be downregulated in inflamed IBD mucosa, may highlight an important functional pathway in intestinal immune homeostasis and represent a potential future therapeutic target in IBD.
      Keyword(s):
      Thesis main supervisor(s):
      Thesis co-supervisor(s):
      Degree grantor:
      Language:
      en

      Institutional metadata

      University researcher(s):
      Academic department(s):

        Record metadata

        Manchester eScholar ID:
        uk-ac-man-scw:317360
        Created by:
        Shuttleworth, Elinor
        Created:
        25th November, 2018, 23:15:05
        Last modified by:
        Shuttleworth, Elinor
        Last modified:
        9th January, 2019, 09:54:04

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