Macrophages in Nematode Infection: Regulators, Effectors or Healers?
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Biological Sciences
Abstract
Macrophages are cells found in abundance in all tissues of the body that participate in a wide range of essentials functions through their ability to respond to signals in the local environment. T cells, which orchestrate the immune response to infection, are a key source of these signals. In response to microbial infections, T cells produce signals that ?classically-activate? macrophages to become very effective at killing intracellular bacteria. In contrast, when an individual is infected with worms T cells produce signals that ?alternatively-activate? macrophages. The function of alternatively activated macrophages (AAMac) is poorly understood but data suggests they are involved in dampening down inflammation and mediating wound repair. The possibility that they also act as cells that can kill extra-cellular parasites such as worms has not been directly addressed. AAMac have now been found in a variety of chronic disease conditions including asthma, lung fibrosis and cancer but their role has not been clearly defined. We propose to address 1) whether AAMac have direct anti-worm function, 2) whether they induce regulatory pathways associated with chronic infection and 3) whether they mediate repair of wounds caused by tissue-migrating worms. By focussing on the normal function of these cells during worm infection we hope to reveal the appropriate roles of these cells and thus address which of products of AAMac may be useful as targets in treatment of chronic diseases. These studies will also help in the design of vaccines against worms that cause debilitating infections in millions of people in the tropics.
Technical Summary
Macrophages are a key effector cells during innate immunity and are important targets of T-cell derived cytokines during adaptive immune responses. Macrophages exposed to Th1 cytokines or microbial signals have been termed classically-activated macrophages (CAMac), while those that respond to the Th2 cytokines IL-4 and IL-13 are referred to as alternatively-activated (AAMac). The essential role of CAMac in the control of intracellular pathogens is well documented and has been extensively researched in vitro and in vivo. In contrast far less is known about AAMac function, especially in vivo. Recent data suggests AAMac have both regulatory and wound healing properties but their roles as effectors against extra-cellular pathogens is still speculative. We propose to use helminth infection models to directly address these functions in vivo. We aim to address 1) whether AAMac have direct anti-parasitic function, 2) whether they induce regulatory pathways associated with chronic infection and 3) whether they mediate tissue repair associated with tissue-migrating helminths. The AAMac vs. CAMac paradigm is unlikely to prove sufficient to explain the many functions of macrophages during Th2 mediated immune responses. Thus, our final aim is to address the in vivo signals beyond Th2 cytokines that are necessary to mediate these functions. For each of the three functional settings to be studied ? effector mechanisms, regulation, and healing ? a common set of experimental approaches will be employed. As a starting point, we will use selective depletion of macrophages at specific time points during infection. In many situations we will be able to target depletion to a particular site as well. In parallel, we will use mice in which the IL-4Ralpha is absent only on macrophages and granulocytes allowing us to address the requirement for alternative activation. Additional macrophage-specific KOs, specific inhibitors and neutralizing antibodies and reconstitution/rescue experiments will address whether a particular macrophage product or signaling pathway is required. Finally mixed bone marrow chimeric mice, will allow us to address the balance of AAMac vs. CAMac that determine disease outcome as well as the importance of antigen presentation by AAMac.
Publications
Mylonas KJ
(2013)
Alternative activation of macrophages by filarial nematodes is MyD88-independent.
in Immunobiology
Cook PC
(2012)
Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo.
in Proceedings of the National Academy of Sciences of the United States of America
Sutherland TE
(2011)
Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor.
in Chemistry & biology
Fairlie-Clarke KJ
(2010)
Antibody isotype analysis of malaria-nematode co-infection: problems and solutions associated with cross-reactivity.
in BMC immunology
Decaestecker E
(2011)
Candidate innate immune system gene expression in the ecological model Daphnia.
in Developmental and comparative immunology
Appleby LJ
(2012)
Chitinase 3-like 1 protein levels are elevated in Schistosoma haematobium infected children.
in PLoS neglected tropical diseases
Sutherland TE
(2009)
Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies.
in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
Hughes K
(2012)
Conditional deletion of Stat3 in mammary epithelium impairs the acute phase response and modulates immune cell numbers during post-lactational regression.
in The Journal of pathology
Babayan SA
(2012)
Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes.
in PLoS neglected tropical diseases
Davies LC
(2013)
Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation.
in Nature communications
Allen JE
(2011)
Diversity and dialogue in immunity to helminths.
in Nature reviews. Immunology
Appleby LJ
(2015)
Down Regulation of the TCR Complex CD3?-Chain on CD3+ T Cells: A Potential Mechanism for Helminth-Mediated Immune Modulation.
in Frontiers in immunology
Allen JE
(2011)
Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens.
in PLoS pathogens
Babayan SA
(2010)
Filarial parasites develop faster and reproduce earlier in response to host immune effectors that determine filarial life expectancy.
in PLoS biology
Babayan SA
(2012)
Future prospects and challenges of vaccines against filariasis.
in Parasite immunology
Jenkins SJ
(2013)
IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1.
in The Journal of experimental medicine
Jenkins SJ
(2011)
Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.
in Science (New York, N.Y.)
Rückerl D
(2014)
Macrophage proliferation, provenance, and plasticity in macroparasite infection.
in Immunological reviews
Specht S
(2012)
Over expression of IL-10 by macrophages overcomes resistance to murine filariasis.
in Experimental parasitology
Jenkins SJ
(2010)
Similarity and diversity in macrophage activation by nematodes, trematodes, and cestodes.
in Journal of biomedicine & biotechnology
Appleby LJ
(2013)
Sources of heterogeneity in human monocyte subsets.
in Immunology letters
Whyte CS
(2011)
Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function.
in Journal of leukocyte biology
Van Der Werf N
(2011)
Th2 responses to helminth parasites can be therapeutically enhanced by, but are not dependent upon, GITR-GITR ligand costimulation in vivo.
in Journal of immunology (Baltimore, Md. : 1950)
Hewitson JP
(2014)
The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo.
in PLoS pathogens
Davies LC
(2013)
Tissue-resident macrophages.
in Nature immunology
Gause WC
(2013)
Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths.
in Nature reviews. Immunology
Díaz A
(2011)
Understanding the laminated layer of larval Echinococcus II: immunology.
in Trends in parasitology
| Description | Programme Grant |
| Amount | £1,595,000 (GBP) |
| Funding ID | MR/K01207X/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2013 |
| End | 01/2018 |
| Description | Project grant as part of an international network |
| Amount | £350,000 (GBP) |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 03/2010 |
| End | 02/2014 |
| Description | Wellcome Trust Project Grant (Induction of tolerogenic dendritic cells by the laminated layer of Echinococcus granulosus) |
| Amount | £182,777 (GBP) |
| Funding ID | 092752 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2010 |
| End | 03/2015 |
| Description | SOCS |
| Organisation | University of Aberdeen |
| Department | Institute of Applied Health Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | provided in vivo models to study SOCS proteins in macrophages |
| Collaborator Contribution | added greater understanding to our research on macrophage activation |
| Impact | Research article published in Journal of Leukocyte Biology |
| Start Year | 2008 |
| Description | Uruguay |
| Organisation | University of the Republic |
| Country | Uruguay |
| Sector | Academic/University |
| PI Contribution | intellectual input and joint grant writing |
| Collaborator Contribution | Joint funding resulted in a PhD student coming from Uruguay to work in my lab for 9 months. |
| Impact | A Royal Society Joint International project grant. Publication: 18000958 |
| Start Year | 2007 |
| Description | Newspaper and Magazine articles |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | A press release on our paper in PLOS Biology was printed in editions of several Scottish Newspapers as well as New Scientist magazine. Many more online journals covered the story. None yet that we are aware of |
| Year(s) Of Engagement Activity | 2010 |
| Description | SciencePaperPodCast |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | PodCast is available on iTunes in which our Science paper is discussed. Number of downloads is unknown but many people mentioned hearing it. none |
| Year(s) Of Engagement Activity | 2011 |