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A Decoy Receptor 3 Analogue Reduces Localised Defects in Phagocyte

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A Decoy Receptor 3 Analogue Reduces Localised Defects in Phagocyte Respiratory infection Thorax: first published as 10.1136/thoraxjnl-2012-201591 on 26 June 2012. Downloaded from ORIGINAL ARTICLE A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia Helen M Marriott,1 Marc Daigneault,1 Alfred A R Thompson,1,2 Sarah R Walmsley,1,2 Sharonjit K Gill,1 Derrick R Witcher,3 Victor J Wroblewski,4 Paul G Hellewell,5 Moira K B Whyte,1,2 David H Dockrell1,2 < Additional materials are ABSTRACT published online only. To view Background Therapeutic strategies to modulate the host Key messages these files please visit the response to bacterial pneumonia are needed to improve journal online (http://dx.doi.org/ 10.1136/ outcomes during community-acquired pneumonia. This What is the key question? thoraxjnl-2012-201591) study used mice with impaired Fas signalling to examine < Does tumour necrosis factor (TNF) superfamily susceptibility to pneumococcal pneumonia and decoy 1Department of Infection and member signalling modify outcomes of pneu- Immunity, University of receptor 3 analogue (DcR3-a) to correct factors mococcal pneumonia? Sheffield, Sheffield, UK associated with increased susceptibility. 2Sheffield Teaching Hospitals, Methods Wild-type mice and those with varying What is the bottom line? Sheffield, UK < 3 degrees of impairment of Fas (lpr) or Fas ligand signalling The balance of Fas ligand and decoy receptor 3 Biotechnology Discovery (gld) were challenged with Streptococcus pneumoniae inhibitable ligands influences T-cell activation Research, Lilly Research Laboratories, Eli Lilly & and microbiological and immunological outcomes and local neutrophil function in the lung during Company, Lilly Corporate measured in the presence or absence of DcR3-a. pneumococcal pneumonia. Center, Indianapolis, Indiana, Results During established pneumonia, neutrophils USA became the predominant cell in the airway and gld mice Why read on? 4Department of Drug Disposition < Immunomodulation of TNF superfamily signal- Development/ were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary ling has potential as immunotherapy during Commercialization, Lilly community-acquired pneumonia. Research Laboratories, Eli Lilly & neutrophil function in comparison to lpr or wild-type Company, Lilly Corporate mice. T-cells from gld mice had enhanced activation and Center, Indianapolis, Indiana, reduced apoptosis in comparison to wild-type and http://thorax.bmj.com/ USA lpr 5 mice during established pneumonia. Treatment with Department of Cardiovascular fl Science, University of Sheffield, DcR3-a reduced T-cell activation and corrected the (FasL, TNFSF6) in uences susceptibility to pneu- Sheffield, UK defect in pulmonary bacterial clearance in gld mice. mococcal pneumonia. FasL is a transmembrane Conclusions The results suggest that imbalance in protein that signals through Fas (CD95, TNFRSF6).2 Multimerised Fas activates apoptosis Correspondence to tumour necrosis factor superfamily signalling and excessive in a range of cells, including epithelial cells and Dr Helen Marriott, Department T-cell activation can impair bacterial clearance in the lung 3 of Infection and Immunity, but that DcR3-a treatment can reduce T-cell activation, phagocytes, regulating immune homeostasis. University of Sheffield Medical Alternatively Fas signal transduction contributes to restore optimal pulmonary neutrophil function and enhance on September 23, 2021 by guest. Protected copyright. School, Beech Hill Road, fl bacterial clearance during S pneumoniae infection. cell activation and pro-in ammatory effects, for Sheffield S10 2RX, UK; h.m. example in the lung FasL contributes to the path- marriott@sheffield.ac.uk ogenesis of acute lung injury.4 FasL expression 56 Received 5 January 2012 increases during pneumococcal infection. During Accepted 29 May 2012 INTRODUCTION pneumonia with Gram-positive bacteria there is Published Online First Streptococcus pneumoniae (the pneumococcus) is the less neutrophil recruitment in lpr mice, which have 26 June 2012 commonest cause of community-acquired pneu- low levels of functional Fas, or in mice treated with monia (CAP) and causes approximately 2 million a decoy receptor 3 analogue (DcR3-a) that deaths annually.1 Despite advances in antimicrobial neutralises FasL.67Despite this, bacterial clearance therapy and management of critically ill patients, is enhanced unless a more severe infection is therapeutic modulation of the pulmonary inflam- established, suggesting under certain circumstances matory response has been relatively neglected in FasL has an adverse effect on disease outcome.6 CAP, even though dysregulation of the inflamma- FasL therefore has key roles in immune homeo- tory response is a key feature of pathogenesis. To stasis,8 and host defence.9 It also has the potential adopt this strategy we need a better understanding to exacerbate inflammatory lung injury, and its role of factors which regulate susceptibility to CAP, and in bacterial clearance varies depending on the how these can be manipulated to ensure an optimal infection and murine model studied.67 inflammatory response that achieves bacterial We addressed the role of FasL in the pathogenesis clearance without inflammatory lung injury. of CAP in murine models of pneumococcal pneu- The tumour necrosis factor superfamily (TNFSF) monia (see online supplement). We tested the regulates inflammatory responses. In this study we role of complete FasL deficiency using C57BL/6 have addressed whether TNFSF member Fas ligand gld mice, which express FasL lacking functional Thorax 2012;67:985–992. doi:10.1136/thoraxjnl-2012-201591 985 Respiratory infection Thorax: first published as 10.1136/thoraxjnl-2012-201591 on 26 June 2012. Downloaded from activity.10 The results were compared with wild-type C57BL/6 Apoptosis was measured as the percentage of cells with hypo- mice and C57BL/6 mice carrying the lpr mutation, which results diploid DNA after propidium iodide staining.19 Analysis was with in reduced expression of Fas,11 but less than complete inhibition FlowJo software V.9.3.2 (Tree Star, Inc, Ashland, Oregon, USA). of Fas signalling, since the mutation is leaky.12 13 We also compared results in these mice with the effect of FasL neutral- Statistics isation with DcR3-a. DcR3-a is an analogue of DcR3 Statistical analysis was by analysis of variance (parametric data), (TNFRSF6B) which neutralises FasL but also inhibits two other t test (parametric data), KruskaleWallis (non-parametric data), TNFSF members: TNFSF14 (lymphotoxin-related inducible ManneWhitney (non-parametric data) or log-rank test for ligand which competes for glycoprotein D binding to herpes survival, using Prism 5.0 software (GraphPad Inc, La Jolla, virus entry mediator on Tcells; LIGHT) and TNFSF15 (TNF-like California, USA). Differences were considered significant if p<0.05. e protein 1A; TL1A).14 16 This allowed us to compare the effects of selective versus non-selective FasL neutralisation that also RESULTS included other TNFSF members to determine their potential role Reduced bacterial clearance in gld mice with established in the pathogenesis of CAP and to examine the therapeutic pneumonia potential of manipulation of TNFSF signalling during CAP. We examined the outcome of infection using three models of Our murine models suggest inhibition of FasL signalling infection with high inocula of S pneumoniae. There was an enhances T-cell activation and impedes bacterial clearance but increase in CFUs in lung and blood, 24 h after infection, in the that these alterations can be corrected by administration of gld mice compared with C57BL/6 and lpr mice (which had a TNFSF decoy receptor 3 analogue (DcR3-a). similar CFUs), after both serotype 1 (figure 1A,B) and serotype 2 infection (figure 1D,E). Serotype 4 infections resulted in higher MATERIAL AND METHODS bacterial CFUs in lung or blood of wild-type and lpr mice but the fi fi Animals increase in CFUs for gld mice was not signi cant ( gure 1G,H). gld FasL contributes to CXC chemokine expression in the lung and Adult female mice, homozygous for the FasL mutation (B6Smn. gld lpr lpr to neutrophil recruitment into the airspaces in response to C -Fasl /J) and Fas (B6.MRL-Fas /J), on a C57BL/6 back- 3 a variety of stimuli including pneumococci.6 20 ground (Jackson Laboratories, Bar Harbour, Maine, USA) were We documented used.10 11 C57BL/6 mice were used as wild-type controls. All impaired neutrophil recruitment into the lung in the absence of gld lpr animal experiments were conducted in accordance with the Home Fas signalling in both and mice 24 h after challenge with S pneumoniae fi Office Animals (Scientific Procedures) Act 1986 and approved by serotype 1 ( gure 1C). After infection with the more S pneumoniae the University of Sheffield Ethical Review Committee. virulent serotypes 2 or 4 , neutrophil numbers were similar between strains at 24 h (figure 1F,I). Fas can trigger neutrophil apoptosis.3 Since absolute levels of neutrophil apoptosis Pneumococcal infection model in vivo in the lung are influenced by the rate of apoptosis induc- Pulmonary infection of mice was by direct tracheal instillation tion and the rate of clearance of apoptotic cells, while the as described previously.17 Neutrophil depletion was with 100 mg/ percentage of apoptotic cells is confounded by rates of neutrophil http://thorax.bmj.com/ mouse Gr-1 antibody or isotype control. Decoy receptor treatment recruitment, we measured rates of constitutive apoptosis in vitro. m was with 400 g/mouse DcR3-a or bovine serum
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