title: Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair.
abstract: Helminth parasites can cause considerable damage when migrating through host tissues, thus making rapid tissue repair imperative to prevent bleeding and bacterial dissemination particularly during enteric infection. However, how protective type 2 responses targeted against these tissue-disruptive multicellular parasites might contribute to homeostatic wound healing in the intestine has remained unclear. Here, we observed that mice lacking antibodies (Aid-/-) or activating Fc receptors (Fcrg-/-) displayed impaired intestinal repair following infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb), whilst transfer of immune serum could partially restore chemokine production and rescue wound healing in Aid-/- mice. Impaired healing was associated with a reduced expression of CXCR2 ligands (CXCL2/3) by macrophages (MΦ) and myofibroblasts (MF) within intestinal lesions. Whilst antibodies and helminths together triggered CXCL2 production by MΦ in vitro via surface FcR engagement, chemokine secretion by intestinal MF was elicited by helminths directly via Fcrg-chain/dectin2 signaling. Blockade of CXCR2 during Hpb challenge infection reproduced the delayed wound repair observed in helminth infected Aid-/- and Fcrg-/- mice. Finally, conditioned media from human MΦ stimulated with infective larvae of the helminth Ascaris suum together with immune serum, promoted CXCR2-dependent scratch wound closure by human MF in vitro. Collectively our findings suggest that helminths and antibodies instruct a chemokine driven MΦ-MF crosstalk to promote intestinal repair, a capacity that may be harnessed in clinical settings of impaired wound healing.
authors: Laboratory of Intestinal Immunology, Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Center of Allergy and Environment (ZAUM), member of the German Center for Lung Research (DZL), Technische Universität and Helmholtz Center Munich, Munich, Germany.
authors: Julia
authors: J
authors: Esser-von Bieren
authors: Laboratory of Intestinal Immunology, Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Beatrice
authors: B
authors: Volpe
authors: Laboratory of Intestinal Immunology, Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Duncan B
authors: DB
authors: Sutherland
authors: Laboratory of Cell and Membrane Biology, Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Jérôme
authors: J
authors: Bürgi
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: J Sjef
authors: JS
authors: Verbeek
authors: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Benjamin J
authors: BJ
authors: Marsland
authors: Diet, Genomics, & Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland, United States of America.
authors: Joseph F
authors: JF
authors: Urban
authors: Laboratory of Intestinal Immunology, Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Nicola L
authors: NL
authors: Harris
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007422:Intestines / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000276:immunology* / Q000473:pathology; D009351:Nematospiroides dubius / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology*; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D000909:Antibodies, Helminth; D023063:Receptors, Interleukin-8B