Jukes, P; (2016) The role of Annexin 1 in glomerular inflammation. Doctoral thesis , UCL (University College London).

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Abstract

Annexin 1 is an important mediator in the active process of inflammation resolution. The protein controls leukocyte trafficking to inflammatory sites, promotes their nonphlogistic removal from the tissue and polarises infiltrating macrophages towards a pro-resolving phenotype. ANCA-associated vasculitis (AAV) is characterised by a necrotising glomerulonephritis that develops following neutrophil infiltration, accumulation of macrophages and T lymphocytes, and formation of cellular glomerular crescents. The aim of this thesis is to address whether Annexin 1 might play a beneficial role in the resolution of glomerular inflammation in AAV. In the following experiments I examined the effect of the genetic absence of Annexin 1 in two murine models of crescentic glomerulonephritis; nephrotoxic nephritis (NTN) and anti-myeloperoxidase associated glomerulonephritis (murine experimental vasculitis/MEV). In addition, the relationship between Annexin 1 cleavage and proteinase 3 expression was investigated in neutrophils and the ability of a PR3-cleavage resistant Annexin 1 peptide (SuperAnnexinA1) to inhibit neutrophil activation was examined to understand the potential role of Annexin 1 in AAV. Annexin 1 deficiency resulted in a significant exacerbation of disease severity in the NTN model, and administration of SuperAnnexinA1 polarised infiltrating macrophages towards a less inflammatory phenotype. The disease penetrance across experimental groups in the MEV model was not substantial enough to conclude whether the absence of Annexin 1 had an effect on disease. In vitro, there was a significant correlation observed between an increased proportion of PR3high neutrophils and abundance of Annexin 1 cleavage products in neutrophils from healthy controls and PR3-ANCA positive AAV patients. The activation of human neutrophils was inhibited in a dose-dependent manner by increasing concentrations of SuperAnnexinA1. These data indicate that Annexin 1 plays an important protective role in experimental glomerular injury. There is a rationale established to hypothesise an increased degree of Annexin 1 cleavage within an inflamed glomerulus where neutrophils are abundant. This supports the potential for Annexin 1 peptidomimetics to be used in the treatment of glomerular injury.

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