Immune Antibodies and Helminth Products Drive CXCR2-Dependent Macrophage-Myofibroblast Crosstalk to Promote Intestinal Repair.

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

Immune Antibodies and Helminth Products Drive CXCR2-Dependent Macrophage-Myofibroblast Crosstalk to Promote Intestinal Repair

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

Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection

Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations

Modulation of the immune response by nematode secreted acetylcholinesterase revealed by heterologous expression in Trypanosoma musculi

Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host

Parasite mediated protection against allergy.

hroughout evolution, mammals have been exposed to large multicellular worm parasites (helminths). This co-evolution has resulted in a well-balanced network of host-parasite interactions that shape the host’s immune system. In particular, helminth parasites have acquired an impressive repertoire of immunomodulatory strategies to ensure their own survival and reproduction whilst avoiding excessive harm to their host. Moreover, work over the recent decades has shown that the immunomodulatory potential of helminths may not only entail an intriguing capacity for immune evasion, but also provide a means to protect against chronic inflammatory diseases. Allergy is driven by pathological type 2 immune responses, including type 2 cytokine production, IgE class switching, mast cell activation as well as eosinophil recruitment and activation, which are also at play during helminth infection. The overlap between pathological mechanisms of allergy and protective immune mechanisms targeted at parasite killing or expulsion may provide an (evolutionary) explanation for the potential of helminths to suppress allergic inflammation. This chapter will describe the epidemiological and mechanistic basis of parasite-mediated protection against allergy with a focus on the cellular mechanisms employed by helminth parasites to suppress type 2 inflammation

Immune-regulation and -functions of eicosanoid lipid mediators.

Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-gamma shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation

Eicosanoids in tissue repair.

Trauma or infection can result in tissue damage, which needs to be repaired in a well-orchestrated manner to restore tissue function and homeostasis. Lipid mediators derived from arachidonic acid (termed eicosanoids) play central and versatile roles in the regulation of tissue repair. Here, I summarize the current state-of the-art regarding the functional activities of eicosanoids in tissue repair responses during homeostasis and disease. I also describe how eicosanoids are produced during tissue damage and repair in a time-, cell- and tissue-dependent fashion. In particular, recent insights into the roles of eicosanoids in epithelial barrier repair are reviewed. Furthermore, the distinct roles of different eicosanoids in settings of pathological tissue repair such as chronic wounds, scarring or fibrosis are discussed. Finally, an outlook is provided on how eicosanoids may be targeted by future therapeutic strategies to achieve physiological tissue repair and prevent scarring and loss of tissue function in various disease contexts

Not just "leuko" after all: Epithelial leukotriene production in type 2 immunity.

New research shows that specialized epithelial cells (tuft cells) are major producers of lipid mediators (leukotrienes) that drive allergic inflammation and host defense against helminth parasites. (See the related Research Article by Ualiyeva et al.

Trained immunity in type 2 immune responses.

Immunological memory of innate immune cells, also termed "trained immunity", allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation

Correction to: Trained immunity in type 2 immune responses (Mucosal Immunology, (2022), 10.1038/s41385-022-00557-0).

The original version of this article unfortunately contained a mistake in the figure legends as the following statement was missing “Created with BioRender.com”. The original article has been corrected