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.

Clinical Association of Chemokine (C-X-C motif) Ligand 1 (CXCL1) with Interstitial Pneumonia with Autoimmune Features (IPAF)

“…Neutrophils, readily identified by the expression of MPO, are the predominant CXCR2+ cells among blood leukocytes, and CXCR2 is a key regulator of their recruitment and effecting responses3. In conjunction with the observation of the increased circulating concentration of CXCL1, it is highly likely that the CXCL1-CXCR2 axis was involved in the focal accumulations of neutrophils that were found in IPAF lungs here and in other reports8202122232425.…”

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 + Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

“…Hoeksema et al showed that Trichuris suis soluble products evoke an M2-type macrophage via epigenetic changes (42). Also, macrophages cotreated with Ascaris suum E/S products and immune serum displayed enhanced wound-healing activity in an in vitro model (62). Thus, we speculate that monocytes recruited into the peritoneal cavity are converted into immunoregulatory monocyte-like cells by exposure to the HdAg and/or released host factors, and that these cells represent another mechanism by which HdAg treatment could ameliorate colitis.…”

Diversity and functions of intestinal mononuclear phagocytes

“…154,191 Recovery from Heligmosomoides polygyrus induced intestinal pathology also involves m producing chemokine ligands for CXCR2 on fibroblasts, driven in part via CD64. 192 The ability of m to induce IL-22 production by ILC3 also favours restitution of a damaged epithelial barrier, 80,193 while TGF R mediated suppression of IL-33 production by m has been proposed to mediate resolution of chemical colitis. 190 Arginase produced by alternatively activated m in parasite infections is a further important tissue repair mechanism under these conditions.…”