"Every cell is an immune cell; contributions of non-hematopoietic cells to anti-helminth immunity"

Abstract

Helminths are remarkably successful parasites that can invade various mammalian hosts and establish chronic infections that can go unnoticed for years despite causing severe tissue damage. To complete their life cycles, helminths migrate through multiple barrier sites that are densely populated by a complex array of hematopoietic and non-hematopoietic cells. While it is clear that type 2 cytokine responses elicited by immune cells promote worm clearance and tissue healing, the actions of non-hematopoietic cells are increasingly recognized as initiators, effectors and regulators of anti-helminth immunity. This review will highlight the collective actions of specialized epithelial cells, stromal niches, stem, muscle and neuroendocrine cells as well as peripheral neurons in the detection and elimination of helminths at mucosal sites. Studies dissecting the interactions between immune and non-hematopoietic cells will truly provide a better understanding of the mechanisms that ensure homeostasis in the context of helminth infections.

Figure 1.

Potential mechanisms for helminth detection by the host. (1) Established evidence indicates that helminth-induced type 2 inflammation is initiated by alarmins (IL-25, IL-33, and TSLP) and DAMPs released by dying epithelial cells. (2) However, recent evidence suggests that tuft cells (TC), specialized chemosensory cells in mucosal barriers may potentially respond to helminth-derived signals or metabolites from a helminth-altered microbiome, which causes TC release of IL-25 and cysLT. (3) There is also evidence suggesting that stromal cell (SC) niches can trigger type 2 inflammation by an IL-33-dependent mechanism. However, it is unclear if IL-33 is released by SC, either while still alive (teal) or during cellular death (gray). (4) Cholinergic neurons (Neu) exposed to helminth-derived products in vitro can release the neuropeptide NMU. But, it is unclear if neighboring cells (e.g. TC) can signal to neurons during helminth infection.

Figure 2.

Non-hematopoietic cells contribute to anti-Helminth mechanisms and tissue repair. (A, left) Epithelial (EC), goblet (GC), and Paneth cells (PC) secrete factors that directly affect helminths. (B) Worm expulsion from the GI tract is accomplished by several coordinated mechanisms: mucus secretion by GC, smooth muscle cell (SMC) contraction controlled by cholinergic neurons (Neu) and serotonin (5-HT) from enterochromaffin cells (EECs), among other cell types, and growth of the villi to push worms off the “epithelial escalator”. The intestinal stem cell niche (ISC) at the base of the villi controls cellular expansion and differentiation of specialized secretory cell types (e.g. tuft cells, TC, and PC) needed for the epithelial escalator and mucus secretion effector functions. (C) GCs contribute to tissue repair by secreting TFFs that can promote EC proliferation. ECs and macrophages (Mac) synergistically promote collagen deposition by myofibroblasts to repair damaged tissues.

Figure 3.

Regulation of Helminth infection by enterochromaffin cells (EECs), neurons, and neuronal mediators. (A) most work in the GI tract has examined multiple cellular sources of neurotransmitters serotonin (5-HT) and acetylcholine (Ach), including ILC2s, tuft cells, and EECs. IL-33-evokes 5-HT release in ILC2 and EECs. Serotonergic neurons (purple) activate cholinergic neurons (orange), which regulates the ISC. Ach can act on and be released by ILC2s, which also receive NMU signals from peptidergic neurons (red). Both inputs evoke the release of IL-13 from ILC2s. It is possible that some helminths may secrete AChEs to deplete Ach gradients in tissues. (B) Non-peptidergic neurons of the Mrgpr class (E, F) are reduced in density around encysted Sm eggs, but their role is unclear. (C) In the airway, ILC2s are positively regulated by NMU, while NMB and CGRP tend to inhibit their proliferation and type 2 cytokine secretion (although CGRP does not inhibit IL-5 secretion). Basophils induce the upregulation of the NMBR on ILC2s. The exact cellular source of CGRP and NMB are not clear. (D) Very little is known regarding multicellular crosstalk during helminth skin penetration, or if this is modulated by helminth E/S products.