Similarly, infection with soil-transmitted helminths including has been associated with increased insulin sensitivity (50). and has been well-described in herb systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular MK-8745 networks that support disease tolerance during enteric stages of parasitic helminth contamination and why this option host defense strategy may have developed to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine. and the hookworm in a laboratory setting have exhibited that upon access into the intestine, epithelial cells (IECs) are critical for initiating a type 2 immune response. IECs release damage-associated molecules such as ATP as well as the cytokines interleukin (IL)-25 and thymic stromal lymphopoietin that, in combination with diverse sources of IL-33, stimulate tissue-resident type 2 innate lymphoid cells (ILC2s) to produce IL-4, IL-5, and IL-13 (10C14). These quintessential type 2 cytokines rapidly recruit eosinophils and alternatively activated macrophages (AAMacs) with tissue-reparative properties to the site of contamination that feedback on to the epithelium to fortify the intestinal barrier by stimulating the production of mucus and anti-microbial peptides as well as enhancing the shedding of lifeless enterocytes (10). Even though mechanisms by which IECs detect helminth contamination remain largely undefined, recent studies exhibited that succinate, derived from the metabolism of dietary fibers by intestinal spp., is usually detected by a specialized subset of IL-25 generating chemosensory IECs called tuft cells. Succinate stimulated tuft cell proliferation (and therefore increased amounts of intestinal IL-25) in a succinate receptor (Sucnr1)-dependent manner. Increased IL-25 stimulated the proliferation of IL-13 generating ILC2s that, in turn, induced goblet cell hyperplasia, intestinal remodeling, and enhanced immunity to subsequent infection (15C17). Importantly, succinate signals were not required for worm expulsion. These results support the fascinating possibility that metabolic signals, while not necessarily critical for host resistance, provide an important pathway used by the host to promote tissue repair and disease tolerance to contamination. In parallel to ILC2 activation, has been shown to stimulate production of thymic stromal lymphopoietin by IECs that condition intestinal dendritic cells (DCs) en route to the draining lymph nodes to polarize CD4+ T cells into Th2 cells that home to the intestine and amplify the ongoing type 2 response (18). DCs have also been shown during MK-8745 contamination to initiate the differentiation of T follicular helper cells that migrate to the B cell follicles and drive a humoral immune response skewed toward the generation of IgG1 and IgE antibody-secreting plasma cells (19, 20). This antibody response enhances the effector functions of macrophages, mast cells and basophil populations through Fc-mediated clearance of cellular debris and release of histamines and eicosanoids that maintain or enhance gut contractility and intestinal blood flow (21C23). Helminth-specific immunoglobulins have also been shown to directly bind and limit parasite motility (21, 24), the latter being necessary for parasite survival. The importance of the type 2 immunity in response to tissue injury is usually underscored by a seminal study by Loke and Allen demonstrating that incision of the peritoneal cavity of mice was sufficient to induce transient IL-4R-dependent AAMac polarization (25). This work has been recently supported and expanded upon in human vascular disease (26), a zebrafish model of tissue regeneration (27) and mouse models of acute skin (28), liver (29), and muscle mass injuries (30) where IL-4/IL-13 signals promote clearance of cellular debris and tissue healing by structural cells and AAMacs. Collectively, these results suggest that type 2 immunity is usually a part of a conserved tissue repair program co-opted to limit tissue damage and support barrier integrity during helminth contamination. For an in-depth examination of type 2 immunity in tissue repair, we refer you to recent reviews (31, 32). It is important to note, however, that innate responses to Adam30 the tissue invasive stages of helminth contamination may not be exclusively type 2 immune-driven. For example, Klein and colleagues recently exhibited that following larvae invasion into the duodenal mucosa, production MK-8745 of a quintessential type 1 cytokine, IFN,.
