Role of a Novel Scavenger Receptor in Epithelial Inflammatory Responses

Lead Research Organisation: University of Oxford
Department Name: Medical Sciences Division

Abstract

The immune system protects us from infection. When we are exposed to an infection for the first time the so-called ?innate? immune system is responsible for detecting and responding to bacteria and viruses and other particles that enter the body. The innate system also serves help the so-called ?acquired? immune system, which prevents re-infection. One activity of innate immune is the generation of an inflammatory response. This is important for fighting infection, but if this response is not controlled properly severe disease results (for example, asthma and chronic obstructive inflammatory disease in the lung).The functioning of innate immune system is dependent upon the expression of molecules on the surface of immune system cells, known as pattern recognition receptors. These molecules are able to sense pathogens and trigger an appropriate immune response to get rid of the infection. Because of its large surface area, the lung is a major site where disease-causing airborne microbes and other agents enter the body. The lung is lined by specialised cells (epithelial cells), which provide not only a physical barrier but also play an important role in innate immunity (e.g. they produce substances that help kill bacteria). However, we have a very limited understanding of these pattern recognition receptors they express and how they function to keep the lung healthy.
In this grant, we propose to study a newly identified epithelial-specific pattern recognition receptor and see how it is involved in epithelial inflammatory responses. This receptor is only expressed on certain epithelial cells, including some within the lung. We will investigate the nature of pro-inflammatory agents it can recognise and the consequences of altering the expression of the receptor on epithelial inflammatory responses. This research will help us to understand how the health of the lung is normally maintained and what may go wrong in specific disease conditions. It may also reveal new ways to treat inflammatory lung diseases.

Technical Summary

We aim to study the contribution of a novel pattern recognition receptor (PRR) to the regulation of inflammatory responses of airway epithelia. Epithelia separate the internal milieu of the host from the external environment, present a physical barrier to the entry of pathogens and play crucial roles in initiating and augmenting host defense mechanisms. Because of its very large surface area, the human lung is exposed to great volumes of pathogens and other noxious substances via inhalation that have the capacity to induce damaging inflammatory reactions. These agents also can exacerbate underlying inflammatory conditions, such as asthma and chronic obstructive pulmonary disease. Epithelia play a pivotal role in the induction of lung inflammation and injury. However, despite the important contributions of respiratory epithelial cells, our understanding of the mechanisms that regulate their inflammatory responses is relatively poor.
Recently, we identified a novel PRR, a scavenger receptor (SCARA5) that uniquely is epithelial-restricted. Scavenger receptors display unusually broad ligand binding properties. We hypothesise that SCARA5 has important roles in the innate immune activities of epithelia. We have shown in preliminary experiments SCARA5 can recognise lipopolysaccharide (LPS), a component of Gram-negative bacteria and important immunostimulant of innate immune cells. Through the application of anti-SCARA5 antisera we have confirmed that epithelial cell lines that have characteristics of respiratory epithelia express the receptor. We have generated by genetic engineering a mouse strain deficient in SCARA5, which will facilitate studies in vivo and ex-vivo. We hypothesise that SCARA5 is a PRR on airway epithelia that significantly influences their pro-inflammatory responses to LPS and other specific stimuli.
In this proposal we will exploit these data and will address the following questions:
1. What is the diversity of pro-inflammatory molecules recognised by the receptor?
2. Does receptor engagement stimulate specific signalling pathways?
3. Do changes in relative levels of receptor alter epithelial inflammatory responses?
4. How does the receptor influence the cellular uptake and fate of specific pro-inflammatory molecules?
5. What is the pattern of cellular expression of the receptor in vivo?
This programme of research will significantly expand our understanding of the innate immune mechanisms of airway epithelia and has the potential to identify roles for this PRR in pathological processes that may be a therapeutic target.

Publications

10 25 50

publication icon
Bedard M (2019) Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells. in Proceedings of the National Academy of Sciences of the United States of America

publication icon
Chen YL (2020) Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation. in The Journal of experimental medicine

 
Title Epithelial cell lines over expressing isotypes of SCARA5 
Description We have generated mammalian cell lines that over express the scavenger receptor SCARA5 in an inducible fashion. 
Type Of Material Cell line 
Provided To Others? No  
Impact We have been able to investigate the biological activities of this novel receptor leading to a reduction in our animal usage in experiments 
 
Title Novel genetically modified mouse strain 
Description We have generated a genetically modified mouse strain (knock out mouse) which lacks the scavenger receptor. A breeding colony of these mice has been established in a biomedical facility at UNiversity of Oxford. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This mouse model is greatly facilitating our studies of the biological activities dependent upon the scavenger receptor in vivo. 
 
Description B cell biology and NKT cells 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative work on the interaction of the innate and adaptive immune responses has led to two publications. We study the role of NKT cells in this interaction.
Collaborator Contribution Collaborative work on the interaction of the innate and adaptive immune responses has led to two publications. The collaborator studies the role of B cells in this interaction.
Impact Publications: 20228797 18550831
Start Year 2007
 
Description Collaboration with the Oxford Vaccine Group 
Organisation University of Oxford
Department Oxford Vaccine Group
Country United Kingdom 
Sector Academic/University 
PI Contribution In the context of the MRC Experimental Medicine Challenge Grant, my group has set up a close collaboration with the Oxford Vaccine Group directed by Professor Andrew Pollard.
Collaborator Contribution As a joint collaboration, we are investigating disease mechanisms in enteric fever to characterise innate and adaptive immunity in mucosa and blood in controlled human infection models
Impact Collaboration still ongoing
Start Year 2014
 
Description Role of lysosome in activation of specific pattern recognition receptors 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Made a novel observation of aberrant activation of a pro-inflammatory innate immune mechanism in a mouse model of a glycosphingolipid storage disease.
Collaborator Contribution Provision of expertise, animal models, co-writing of grant application that led to additional grant funding, co-applicant on successful application to industrial collaborator for provision of llcensed biologic drug which will be tested in the animal models.
Impact This collaboration has resulted in the obtaining of a grant from a US based charity to financially support one aspect of the study and the results obtained to date are the basis of a recently-submitted grant application to MRC. An undergraduate project student is currently contributing to this research and a manuscript is in preparation.
Start Year 2009
 
Description Role of novel scavenger receptor in inflammatory responses of human airways 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided expertise and knowledge as well as specific reagents to the collaboration to facilitate the studies of patient material obtained through clinical consultations
Collaborator Contribution In collaboration with Professor Donna Davies and Dr Marina Leino we are exploring the expression and biological activities of the novel scavenger receptor in the inflammatory responses of ex-vivo airway tissues from healthy and diseased donors.
Impact These collaborative studies are in progress but we anticipate peer-reviewed publication(s) derived from these studies within the next twelve months.
Start Year 2009
 
Description A level student visits 2012 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 students were hosted by members of my group for a "work experience week'

school would like to repeat the program in 2013
Year(s) Of Engagement Activity 2012
 
Description Flow Cytometry Talk for In2Science work experience programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aim was to introduce participants of the WIMM work experience programme to the basic concepts of flow cytometry; audience: high school age participants of the WIMM work experience programme
Year(s) Of Engagement Activity 2018
 
Description Hosting of severl A-level Work Experience students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Group hosted five A-level students from local schools for a period of Work Experience. Two of the students subsequently decided to go on to study medicine.
Year(s) Of Engagement Activity 2019
 
Description MRC Annual Review 2008-09 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact General description of the my research programme to a general audience

general interests towards the research programmes that we are developing in my laboratory and within the MRC Human Immunology Unit.
Year(s) Of Engagement Activity 2009
 
Description MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We set up and organised the "Cancer Immunotherpy Stand" in the context of the yearly MRC Festival of Medical Research
Year(s) Of Engagement Activity 2019
 
Description Magadalen College School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Prof. Cerundolo gave a lecture at Magadalen College School, Oxford to 130 17-year olds on the career path of scientists in which he described training and job opportunities in biomedical research

School interested in future visits
Year(s) Of Engagement Activity Pre-2006
 
Description Oxford Alumni 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Prof. Cerundolo gave a lecture on tumour immunology and cancer vaccines to a group of 130 Oxford Alumni (average age 60 years)

Talk was well received
Year(s) Of Engagement Activity 2009
 
Description Oxford Hands-On Science school visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aim was to share enthusiasm for science with school pupils by taking hands-on science activities into classrooms; audience: local school children
Year(s) Of Engagement Activity 2018
 
Description Oxford Science and Ideas Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Our group set up a Cancer Immunotherapy stand at the Oxford Science and Ideas festival
Year(s) Of Engagement Activity 2019
 
Description Oxford University Department for Continuing Education Human and Veterinary Vaccinology Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact During the last 2 years, the Oxford University Department for Continuing Education http://www.conted.ox.ac.uk/courses/C900-1
has launched a leading educational programme in Vaccinology, tailored to the needs of industry in the UK and beyond, by sharing the expertise of several investigators, both at the Institute for Animal Health and across the University of Oxford, complemented by the views and experience of distinguished outside speakers. The courses run in 2010 were fully subscribed and received very good feedback from the participants. The satisfaction scores were very high: 88% for the Human and Veterinary Vaccinology; 77% for the Clinical Vaccine Development course; and 81% for the Vaccine Biomanufacturing course.
In November 2011 Prof. Cerundolo gave a talk entitled 'An Introduction to Tumour Immunology'

Course was well attended
Year(s) Of Engagement Activity 2011
 
Description School Work Experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Where possible within the constraints of Health & Safety, the Unit welcomes sixth form students to carry out their work experience within the Unit - undertaking simple practical techniques and shadowing Unit members to get a better appreciation of a career in medical research. One student spent 1 week working in my Lab.

School asked for future opportunities
Year(s) Of Engagement Activity 2011
 
Description Volunteering in Settlers Exhibition, Oxford Museum of Natural History 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An Exhibition to raise awareness into DNA and VR
Year(s) Of Engagement Activity 2018