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The Parasitic 68-Mer Peptide Fhhdm-1 Inhibits Mixed Granulocytic Inflammation and Airway Hyperreactivity in Experimental Asthma

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The Parasitic 68-Mer Peptide Fhhdm-1 Inhibits Mixed Granulocytic Inflammation and Airway Hyperreactivity in Experimental Asthma The Parasitic 68-mer Peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma Tanaka, A., Allam, V., Simpson, J., Tiberti, N., Shiels, J., To, J., Lund, M., Combes, V., Weldon, S., Taggart, C., Dalton, J., Phipps, S., Sukkar, M., & Donnelly, S. (2018). The Parasitic 68-mer Peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma. Journal of Allergy and Clinical Immunology, 141(6), 2316-2319. https://doi.org/10.1016/j.jaci.2018.01.050 Published in: Journal of Allergy and Clinical Immunology Document Version: Peer reviewed version Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2018 Elsevier. 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Oct. 2021 Accepted Manuscript The Parasitic 68-mer Peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma Akane Tanaka, BSc, Venkata Sita Rama Raju Allam, MS Pharm, Jennifer Simpson, BBiomedSc, Natalia Tiberti, PhD, Jenna Shiels, BSc, Joyce To, BSc, Maria Lund, PhD, Valery Combes, PhD, Sinead Weldon, PhD, Cliff Taggart, PhD, John P. Dalton, PhD, Simon Phipps, PhD, Maria B. Sukkar, PhD, Sheila Donnelly, PhD PII: S0091-6749(18)30330-0 DOI: 10.1016/j.jaci.2018.01.050 Reference: YMAI 13346 To appear in: Journal of Allergy and Clinical Immunology Received Date: 21 April 2017 Revised Date: 30 December 2017 Accepted Date: 22 January 2018 Please cite this article as: Tanaka A, Allam VSRR, Simpson J, Tiberti N, Shiels J, To J, Lund M, Combes V, Weldon S, Taggart C, Dalton JP, Phipps S, Sukkar MB, Donnelly S, The Parasitic 68-mer Peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma, Journal of Allergy and Clinical Immunology (2018), doi: 10.1016/j.jaci.2018.01.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT 1 The Parasitic 68-mer Peptide FhHDM-1 inhibits mixed granulocytic inflammation and 2 airway hyperreactivity in experimental asthma 3 4 Clinical Implications : 5 Peptides secreted by parasitic worms (helminths) have potential in the treatment of asthma and 6 other respiratory conditions in which eosinophilic and/or neutrophilic inflammation plays a 7 pathological role. 8 9 Capsule Summary 10 A peptide derived from the parasitic worm Fasciola hepatica inhibits eosinophilic and neutrophilic 11 airway inflammation, mucus production and airway hyperreactivity in a murine model of house 12 dust mite induced asthma. 13 14 Key Words: MANUSCRIPT 15 Helminth, Macrophage, House Dust Mite, Lipopolysacc haride, HMGB1, IL-17, Neutrophils, 16 Eosinophils 17 18 Abbreviations: 19 BALF Bronchoalveolar lavage fluid 20 BMDM Bone marrow derived macrophage 21 FhHDM-1 Fasciola hepatica helminth defense molecule 22 LPS LipopolysaccharideACCEPTED 23 IPA Ingenuity Pathway Analysis 24 25 26 ACCEPTED MANUSCRIPT 27 Funding: 28 A Tanaka is supported by an Australian Government Research Training Program Scholarship. 29 VSRR Allam is supported by a University of Technology Sydney Postgraduate Research 30 Scholarship. N Tiberti is supported by the Swiss National Science Foundation (grant n. 31 P300PA_164715). C Taggart and S Weldon are supported by the Medical Research Council. JP 32 Dalton is funded by grants from a European Research Council Advanced Grant (HELIVAC, 33 322725) and is a member of the Horizon 2020-funded Consortium PARAGONE. S Donnelly is 34 funded by the National Health and Medical Research Council Australia (APP1087341). 35 36 Conflicts of Interest: None 37 38 Corresponding Author: 39 A/Prof Sheila Donnelly 40 School of Life Sciences MANUSCRIPT 41 University of Technology, Sydney 42 PO Box 123, 43 Ultimo 2007, NSW, Australia 44 Email: [email protected] 45 Fax: +61 2 9514 8206 46 47 48 ACCEPTED 49 50 51 52 To the Editor, ACCEPTED MANUSCRIPT 53 During infection of their mammalian hosts, parasitic worms (helminths) secrete molecules which 54 modulate the host immune response towards a regulatory phenotype. This ensures the long-term 55 survival of the parasite within its host and also prevents excessive tissue damage mediated by 56 inflammatory immune responses. We reported the identification of a novel immunomodulatory 68- 57 mer peptide secreted by the animal and human parasite Fasciola hepatica , termed F. hepatica 58 helminth defense molecule 1 (FhHDM-1) 1. More recently, we showed that FhHDM-1 ameliorates 59 disease in pre-clinical murine models of type 1 diabetes and multiple sclerosis and therefore 60 represents a new bio-active peptide with potential as a novel anti-inflammatory pharmacological 61 therapeutic 2. 62 63 The mechanism by which FhHDM-1 protects against immune-related inflammatory disorders is yet 64 to be fully elucidated. In studies thus far, we have shown that FhHDM-1 preferentially binds to 65 macrophages over neutrophils and lymphocytes whenMANUSCRIPT administered into the peritoneal cavity of 66 immune competent mice 2. Additionally, the peptide inhibits pro-inflammatory cytokine release in 67 murine and human macrophages in vitro 2, 3 . To pin-point the molecular pathways by which 68 FhHDM-1 exerts its anti-inflammatory effects, we examined global transcriptional changes in 69 murine (Balb/c) bone marrow derived macrophages (BMDMs) treated with a synthetic form of 70 FhHDM-1 for 1 h prior to stimulation with bacterial LPS for either 6 or 24 h. Gene expression was 71 profiled on Agilent microarrays containing probes for 41,346 mouse coding transcripts. This 72 analysis revealed that FhHDM-1 treatment enhanced the expression of 1,363 LPS-regulated genes, 73 and decreased the expressionACCEPTED of 1,491 genes by ≥ 2 fold at 6 h. At 24 h, the expression of 988 LPS- 74 regulated genes was increased and 1,292 genes was decreased by ≥ 2 fold (Fig 1A; Online 75 Repository Table 1). Differentially (-2>fold-change>2, P <0.05 with 5% false discovery rate) 76 expressed genes were analysed using Ingenuity Pathway Analysis (IPA) to identify signalling 77 pathways putatively regulated by FhHDM-1 (Fig 1B). Within the top 20 significantly altered 78 pathways, 16 associated with theA CCEPTEDactivation of MANUSCRIPT pro-inflammatory responses were repressed by 79 FhHDM-1, consistent with its potent anti-inflammatory activity. Notably, IPA analysis predicted 80 that FhHDM-1 inhibits high-mobility group box-1 (HMGB1) signalling and IL-17 mediated allergic 81 inflammation (Fig 1B). The anti-inflammatory effect of the peptide was not specific to Balb/c 82 mice, as BMDMs derived from C57BL6 mice treated with FhHDM-1 showed the same pattern of 83 cytokine suppression in response to LPS (Online Repository Fig E2). 84 85 We have previously shown that HMGB1 is an upstream mediator of the allergic asthmatic response 86 in mice 4, and that neutralisation of this protein protects against allergen-induced eosinophilic and 87 neutrophilic inflammation in experimental asthma 4. IL-17 mediates neutrophilic recruitment to sites 88 of inflammation and is implicated in the neutrophilic asthma phenotype which is relatively resistant 89 to treatment with corticosteroids 5. Accordingly, we hypothesised that FhHDM-1 has therapeutic 90 potential in allergic asthma, and that it would protect against both eosinophilic and neutrophilic 91 responses. MANUSCRIPT 92 93 94 To test our hypothesis, we employed an experimental mouse model of house-dust mite (HDM) 95 induced allergic asthma, as this model elicits a mixed granulocytic inflammatory response 4. 96 C57BL6 mice were sensitized to house dust mite extracts (100 µg) or saline intranasally, and after 2 97 weeks, were challenged daily with house dust mite extracts (5 µg) or saline, respectively, for 4 days 98 (See study design, Fig 2A). Mice received an intravenous injection of FhHDM-1 (5, 10 or 25 µg 99 dose) 30 min prior to each house dust mite exposure during the challenge period only. For 100 comparison, mice ACCEPTEDwere also treated with a homologous helminth defense molecule derived from 101 Schistosoma mansoni (SmHDM-2) or vehicle control (PBS). FhHDM-1, at both the 10 and 25 µg 102 dose significantly attenuated allergen induced eosinophil, neutrophil and lymphocyte numbers in 103 the BALF (Fig 2B). This effect was specific to FhHDM-1, as neither SmHDM-2 nor PBS had any 104 effect on airway inflammation. 105 ACCEPTED MANUSCRIPT 106 Consistent with this anti-inflammatory effect, FhHDM-1 at both the 10 and 25 µg dose significantly 107 attenuated allergen-induced airway hyper-reactivity (Fig 2C, Online Repository Fig E3). FhHDM-1 108 also significantly reduced histological evidence of tissue inflammation and mucus production (Fig 109 2D).
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