Publications by authors named "Tara E Sutherland"

25 Publications

  • Page 1 of 1

IL-13 is a driver of COVID-19 severity.

JCI Insight 2021 Jun 29. Epub 2021 Jun 29.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States of America.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator. Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.
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http://dx.doi.org/10.1172/jci.insight.150107DOI Listing
June 2021

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection.

Life Sci Alliance 2021 08 14;4(8). Epub 2021 Jun 14.

Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

IL-13 is implicated in effective repair after acute lung injury and the pathogenesis of chronic diseases such as allergic asthma. Both these processes involve matrix remodelling, but understanding the specific contribution of IL-13 has been challenging because IL-13 shares receptors and signalling pathways with IL-4. Here, we used infection as a model of acute lung damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. We found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung, and through proteomic and transcriptomic profiling, identified IL-13-dependent changes in matrix and associated regulators. We further showed a requirement for IL-13 in the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 induced cellular stress responses and regulated lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, in the context of acute lung damage, IL-13 has tissue-protective functions and regulates epithelial cell responses during type 2 immunity.
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http://dx.doi.org/10.26508/lsa.202001000DOI Listing
August 2021

IL-13 is a driver of COVID-19 severity.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville VA 22908 USA.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 ( ) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.

Summary: L-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronan's receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.
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http://dx.doi.org/10.1101/2020.06.18.20134353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941663PMC
March 2021

The magnitude of airway remodeling is not altered by distinct allergic inflammatory responses in BALB/c versus C57BL/6 mice but matrix composition differs.

Immunol Cell Biol 2021 Jul 19;99(6):640-655. Epub 2021 Mar 19.

Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.

Allergic airway inflammation is heterogeneous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodeling in asthma, but clinical data suggest that neutralizing type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilized C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodeling. Exposure to an allergen cocktail for up to 8 weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase-like proteins in both C57BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T-cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodeling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen-induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodeling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the extracellular matrix between genetic strains of mice may help us better understand the relationships between lung function, remodeling and airway inflammation.
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http://dx.doi.org/10.1111/imcb.12448DOI Listing
July 2021

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection.

Mucosal Immunol 2020 11 7;13(6):958-968. Epub 2020 Jul 7.

Lydia Becker Institute for Immunology & Infection, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.
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http://dx.doi.org/10.1038/s41385-020-0318-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567645PMC
November 2020

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung.

J Immunol 2019 11 4;203(10):2724-2734. Epub 2019 Oct 4.

Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, Queensland 4878, Australia;

Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, , suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected mice with Unexpectedly, compared with wild-type (WT) mice, infected mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected mice exhibited elevated type 2 gene expression compared with WT mice. Notably, inflammasome activation was not evident early postinfection with , and in contrast to mice, antihelminth responses were unaffected in caspase-1/11-deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 has a role in constraining lung neutrophilia, helminth killing, and type 2 immune responses in an inflammasome-independent manner.
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http://dx.doi.org/10.4049/jimmunol.1900640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826118PMC
November 2019

Crystal-clear treatment for allergic disease.

Science 2019 05;364(6442):738-739

Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1126/science.aax6175DOI Listing
May 2019

The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

Nat Immunol 2019 05 1;20(5):571-580. Epub 2019 Apr 1.

Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.
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http://dx.doi.org/10.1038/s41590-019-0352-yDOI Listing
May 2019

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection.

PLoS Pathog 2018 11 30;14(11):e1007423. Epub 2018 Nov 30.

Lydia Becker Institute for Immunology & Infection, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.
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http://dx.doi.org/10.1371/journal.ppat.1007423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291165PMC
November 2018

Chitinase-like proteins as regulators of innate immunity and tissue repair: helpful lessons for asthma?

Biochem Soc Trans 2018 02 19;46(1):141-151. Epub 2018 Jan 19.

Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, U.K.

Chitinases and chitinase-like proteins (CLPs) belong to the glycoside hydrolase family 18 of proteins. Chitinases are expressed in mammals and lower organisms, facilitate chitin degradation, and hence act as host-defence enzymes. Gene duplication and loss-of-function mutations of enzymatically active chitinases have resulted in the expression of a diverse range of CLPs across different species. CLPs are genes that are increasingly associated with inflammation and tissue remodelling not only in mammals but also across distant species. While the focus has remained on understanding the functions and expression patterns of CLPs during disease in humans, studies in mouse and lower organisms have revealed important and overlapping roles of the CLP family during physiology, host defence and pathology. This review will summarise recent insights into the regulatory functions of CLPs on innate immune pathways and discuss how these effects are not only important for host defence and tissue injury/repair after pathogen invasion, but also how they have extensive implications for pathological processes involved in diseases such as asthma.
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http://dx.doi.org/10.1042/BST20170108DOI Listing
February 2018

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver.

Science 2017 06 11;356(6342):1076-1080. Epub 2017 May 11.

School of Biological Sciences and School of Clinical Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of type 2-mediated macrophage activation. In the lung, surfactant protein A (SP-A) enhanced interleukin-4 (IL-4)-dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury after infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q enhancement of type 2 macrophage activation was required for liver repair after bacterial infection, but resulted in fibrosis after peritoneal dialysis. IL-4 drives production of these structurally related defense collagens, SP-A and C1q, and the expression of their receptor, myosin 18A. These findings reveal the existence within different tissues of an amplification system needed for local type 2 responses.
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http://dx.doi.org/10.1126/science.aaj2067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737834PMC
June 2017

Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

PLoS Pathog 2017 03 23;13(3):e1006233. Epub 2017 Mar 23.

Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.
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http://dx.doi.org/10.1371/journal.ppat.1006233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364000PMC
March 2017

IL-33 delivery induces serous cavity macrophage proliferation independent of interleukin-4 receptor alpha.

Eur J Immunol 2016 10;46(10):2311-2321

School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3FL, UK.

IL-33 plays an important role in the initiation of type-2 immune responses, as well as the enhancement of type 2 effector functions. Engagement of the IL-33 receptor on macrophages facilitates polarization to an alternative activation state by amplifying IL-4 and IL-13 signaling to IL-4Rα. IL-4 and IL-13 also induce macrophage proliferation but IL-33 involvement in this process has not been rigorously evaluated. As expected, in vivo delivery of IL-33 induced IL-4Rα-dependent alternative macrophage activation in the serous cavities. IL-33 delivery also induced macrophages to proliferate but, unexpectedly, this was independent of IL-4Rα signaling. In a filarial nematode infection model in which IL-4Rα-dependent alternative activation and proliferation in the pleural cavity is well described, IL-33R was essential for alternative activation but not macrophage proliferation. Similarly, during Alternaria alternata induced airway inflammation, which provokes strong IL-33 responses, we observed that both IL-4Rα and IL-33R were required for alternative activation, while macrophage proliferation in the pleural cavity was still evident in the absence of either receptor alone. Our data show that IL-33R and IL-4Rα promote macrophage proliferation independently of each other, but both are essential for induction of alternative activation.
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http://dx.doi.org/10.1002/eji.201646442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082546PMC
October 2016

A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.

Nat Commun 2015 Apr 24;6:6920. Epub 2015 Apr 24.

Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.

Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.
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http://dx.doi.org/10.1038/ncomms7920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413429PMC
April 2015

IL-17 and neutrophils: unexpected players in the type 2 immune response.

Curr Opin Immunol 2015 Jun 18;34:99-106. Epub 2015 Mar 18.

Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Charlotte Auerbach Road, Edinburgh EH9 3FL, United Kingdom.

The study of immunity to helminth infection has been central to understanding the function of type 2 cytokines and their targets. Although type 2 cytokines are considered anti-inflammatory and promote tissue repair, they also contribute to allergy and fibrosis. Here, we utilise data from helminth infection models, to illustrate that IL-17 and neutrophils, typically associated with pro-inflammatory responses, are intimately linked with type 2 immunity. Neutrophils work with IL-4Rα-activated macrophages to control incoming larvae but this comes at a cost of enhanced tissue damage. Chitinase like proteins (CLPs) bridge these diverse outcomes, inducing both protective IL-17 and reparative Th2 responses. Dysregulation of CLPs, IL-17 and neutrophils likely contribute to disease severity and pathology associated with type 2 immunity.
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http://dx.doi.org/10.1016/j.coi.2015.03.001DOI Listing
June 2015

Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage.

Nat Immunol 2014 Dec 19;15(12):1116-25. Epub 2014 Oct 19.

Institute of Immunology and Infection Research, Centre for Immunity Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family.
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http://dx.doi.org/10.1038/ni.3023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338525PMC
December 2014

Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation.

Science 2014 Aug 17;345(6196):578-82. Epub 2014 Jul 17.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

The mammalian intestine is colonized by beneficial commensal bacteria and is a site of infection by pathogens, including helminth parasites. Helminths induce potent immunomodulatory effects, but whether these effects are mediated by direct regulation of host immunity or indirectly through eliciting changes in the microbiota is unknown. We tested this in the context of virus-helminth coinfection. Helminth coinfection resulted in impaired antiviral immunity and was associated with changes in the microbiota and STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule that is associated with alternatively activated macrophages, could partially restore antiviral immunity. These data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
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http://dx.doi.org/10.1126/science.1256942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548887PMC
August 2014

Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin.

Semin Immunol 2014 Aug 11;26(4):329-40. Epub 2014 Jul 11.

Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Rα that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury.
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http://dx.doi.org/10.1016/j.smim.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179909PMC
August 2014

Induction of IL-4Rα-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo.

Blood 2012 Sep 1;120(11):2307-16. Epub 2012 Aug 1.

Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Macrophage (MΦ) activation must be tightly controlled to preclude overzealous responses that cause self-damage. MicroRNAs promote classical MΦ activation by blocking antiinflammatory signals and transcription factors but also can prevent excessive TLR signaling. In contrast, the microRNA profile associated with alternatively activated MΦ and their role in regulating wound healing or antihelminthic responses has not been described. By using an in vivo model of alternative activation in which adult Brugia malayi nematodes are implanted surgically in the peritoneal cavity of mice, we identified differential expression of miR-125b-5p, miR-146a-5p, miR-199b-5p, and miR-378-3p in helminth-induced MΦ. In vitro experiments demonstrated that miR-378-3p was specifically induced by IL-4 and revealed the IL-4-receptor/PI3K/Akt-signaling pathway as a target. Chemical inhibition of this pathway showed that intact Akt signaling is an important enhancement factor for alternative activation in vitro and in vivo and is essential for IL-4-driven MΦ proliferation in vivo. Thus, identification of miR-378-3p as an IL-4Rα-induced microRNA led to the discovery that Akt regulates the newly discovered mechanism of IL-4-driven macrophage proliferation. Together, the data suggest that negative regulation of Akt signaling via microRNAs might play a central role in limiting MΦ expansion and alternative activation during type 2 inflammatory settings.
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http://dx.doi.org/10.1182/blood-2012-02-408252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501641PMC
September 2012

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus.

Eur J Immunol 2012 Oct 8;42(10):2667-82. Epub 2012 Aug 8.

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.

Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4(+) CD25(+) Foxp3(-) ) to regulatory (CD4(+) Foxp3(+) ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-α (resistin-like molecule-α). Although HES contains a TGF-β-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations.
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http://dx.doi.org/10.1002/eji.201142161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916998PMC
October 2012

Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor.

Chem Biol 2011 May;18(5):569-79

Centre for Immunity, Infection and Evolution, and the Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Scotland, UK.

Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.
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http://dx.doi.org/10.1016/j.chembiol.2011.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115046PMC
May 2011

Animal models of airway inflammation and airway smooth muscle remodelling in asthma.

Pulm Pharmacol Ther 2009 Oct 23;22(5):455-65. Epub 2009 Apr 23.

Ashworth Laboratory, Institute of Infection and Immunology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Asthma is a complex disease that involves chronic inflammation and subsequent decline in airway function. The widespread use of animal models has greatly contributed to our understanding of the cellular and molecular pathways underlying human allergic asthma. Animal models of allergic asthma include smaller animal models which offer 'ease of use' and availability of reagents, and larger animal models that may be used to address aspects of allergic airways disease not possible in humans or smaller animal models. This review examines the application and suitability of various animal models for studying mechanisms of airway inflammation and tissue remodelling in allergic asthma, with a specific focus on airway smooth muscle.
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http://dx.doi.org/10.1016/j.pupt.2009.04.001DOI Listing
October 2009

Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycin-induced lung fibrosis in mice.

Can J Physiol Pharmacol 2007 Jul;85(7):727-38

Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.

Bleomycin-induced lung fibrosis in mice reproduces some key features of pulmonary fibrosis in humans including alveolar inflammation, myofibroblast proliferation, and collagen deposition. Glucocorticoids have been used as first-line therapy for the treatment of lung fibrosis, although their clinical efficacy is equivocal. We examined the effect of the glucocorticoid, methylprednisolone (MP), and the estrogen metabolite, 2-methoxyestradiol (2MEO) on bleomycin-induced bronchoalveolar inflammation, fibrosis, and changes in lung function. The characterization of the time-course of the bleomycin-induced fibrosis indicated that lung dry mass and hydroxyproline content showed less variance than histopathological assessment of fibrosis. The bleomycin-induced increases in bronchoalveolar lavage (BAL) fluid cell number and protein levels were not significantly influenced by treatment with either MP (1 mg.(kg body mass)(-1).day(-1), i.p.) or 2MEO (50 mg.(kg body mass)(-1).day(-1), i.p.). Lung fibrosis, measured histopathologically or by hydroxyproline content, was not significantly influenced by either MP or 2MEO treatment, whereas the latter agent did reduce the increment in lung dry mass. The enlargement of alveolar airspaces and the decline in lung compliance were exacerbated by MP treatment. These data suggest that bleomycin-induced pulmonary fibrosis is resistant to inhibition by concurrent treatment with either glucocorticoids or 2MEO.
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http://dx.doi.org/10.1139/Y07-065DOI Listing
July 2007

2-Methoxyestradiol--a unique blend of activities generating a new class of anti-tumour/anti-inflammatory agents.

Drug Discov Today 2007 Jul 26;12(13-14):577-84. Epub 2007 Jun 26.

Department of Pharmacology, University of Melbourne, Parkville, Victoria 3010, Australia.

The estradiol metabolite, 2-methoxyestradiol (2MEO), is currently being evaluated in Phase II clinical trials for the treatment of solid tumours and is undergoing preclinical evaluation for inflammatory conditions. The anti-proliferative/cytotoxic/pro-apoptotic effects on tumour and endothelial cells have conferred potential on this metabolite for a synergistic impact on tumour growth. Exploitation of this synergy of 2MEO has previously required the combination of well-established cytotoxic agents with newer anti-angiogenic agents. This article reviews the pharmacology of 2MEO and describes the limitations inherent in its residual estrogen receptor affinity. The extent to which the metabolite 2MEO embodies an optimised therapeutic candidate is discussed. The challenges involved in using rational (3D QSAR-based) drug design to optimise the activity profile of analogues of 2MEO to provide additional members of this new class of anti-tumour/anti-inflammatory drug are also outlined.
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http://dx.doi.org/10.1016/j.drudis.2007.05.005DOI Listing
July 2007

2-methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer.

Clin Cancer Res 2005 Mar;11(5):1722-32

Department of Pharmacology, University of Melbourne, Parkville, Victoria 3010, Australia.

Purpose: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO.

Experimental Design: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver.

Results: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription-PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element-dependent reporter gene that was blocked by ICI 182,780 (1 micromol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth.

Conclusions: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-1789DOI Listing
March 2005
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