The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner

Harnett, M. M. , Doonan, J. , Tarafdar, A., Pineda, M. , Duncombe-Moore, J., Buitrago, G., Pan, P., Hoskisson, P., Selman, C. and Harnett, W. (2024) The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner. Frontiers in Tropical Diseases, 4, 1334705. (doi: 10.3389/fitd.2023.1334705)

Abstract

The parasitic worm-derived immunomodulator, ES-62 rescues defective levels of IL-10-producing regulatory B cells (Bregs) and suppresses chronic Th1/Th17-driven inflammation to protect against joint destruction in the mouse collagen-induced arthritis (CIA) model of rheumatoid arthritis. Such autoimmune arthritis is also associated with dysbiosis of the gut microbiota and disruption of intestinal barrier integrity. We recently further exploited the CIA model to show that ES-62’s prevention of joint destruction is associated with protection of intestinal barrier integrity and normalization of the gut microbiota, thereby suppressing the gut pathology that precedes the onset of autoimmunity and joint damage in CIA-mice. As the status of the gut microbiota impacts on immune responses by influencing haematopoiesis, we have therefore investigated whether ES-62 harnesses the homeostatic mechanisms regulating this gut-bone marrow (BM) axis to resolve the chronic inflammation promoting autoimmunity and joint destruction in CIA. Reflecting this, ES-62 was found to counteract the BM myeloid/lymphoid bias typically associated with chronic inflammation and infection. This was achieved primarily by ES-62 acting to maintain the levels of lymphoid lineages (B220+ and CD3+ cells) observed in naïve, healthy mice but lost from the BM of CIA-mice. Moreover, ES-62’s ability to prevent bone-destroying osteoclastogenesis was found to be associated with its suppression of CIA-induced upregulation of osteoclast progenitors (OCPs) in the BM. Critically, and supporting ES-62’s targeting of the gut-BM axis, this rewiring of inflammatory haematopoiesis was lost in mice with a depleted microbiome. Underlining the importance of ES-62’s actions in restoring steady-state haematopoiesis, the BM levels of B and T lymphoid cells were shown to be inversely correlated, whilst the levels of OCPs positively correlated, with the severity of joint damage in CIA-mice.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Duncombe-Moore, Ms Josephine and Tarafdar, Ms Anuradha and Harnett, Professor Margaret and Pan, Piaopiao and Buitrago, Dr Geraldine and Selman, Professor Colin and Pineda, Dr Miguel and Doonan, Dr James
• Authors: Harnett, M. M., Doonan, J., Tarafdar, A., Pineda, M., Duncombe-Moore, J., Buitrago, G., Pan, P., Hoskisson, P., Selman, C., and Harnett, W.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Frontiers in Tropical Diseases
• Publisher: Frontiers Media
• ISSN: 2673-7515
• ISSN (Online): 2673-7515
• Copyright Holders: Copyright © 2024 Harnett, Doonan, Tarafdar, Pineda, Duncombe-Moore, Buitrago, Pan, Hoskisson, Selman and Harnett
• First Published: First published in Frontiers in Tropical Diseases 4:1334705
• Publisher Policy: Reproduced under a Creative Commons license

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
310084		Does the parasitic worm product, ES-62 sense and homeostatically regulate gut health bia a Breg-NKT cell axis	Margaret Harnett	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/V001027/1	Institute of Biodiversity, Animal Health and Comparative Medicine