Acute infection with the intestinal parasite Trichuris muris has long‐term consequences on mucosal mast cell homeostasis and epithelial integrity

Abstract

A hallmark of parasite infection is the accumulation of innate immune cells, notably granulocytes and mast cells, at the site of infection. While this is typically viewed as a transient response, with the tissue returning to steady state once the infection is cleared, we found that mast cells accumulated in the large-intestinal epithelium following infection with the nematodeTrichuris muris and persisted at this site for several months after worm expulsion. Mast cell accumulation in the epithelium was associated with the induction of type-2 immunity and appeared to be driven by increased maturation of local progenitors in the intestinal lamina propria. Furthermore, we also detected increased local and systemic levels of the mucosal mast cell protease MCPt-1, which correlated highly with the persistent epithelial mast cell population. Finally, the mast cells appeared to have striking consequences on epithelial barrier integrity, by regulation of gut permeability long after worm expulsion. These findings highlight the importance of mast cells not only in the early phases of infection but also at later stages, which has functional implications on the mucosal tissue. Keywords:Acute parasite infection r Large-intestinal epithelium r MCPt-1 r Mucosal mast cell r Trichuris muris Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe intestinal epithelium acts as a barrier to invading pathogens, thus being important for host defense and maintenance of homeostasis. Critical for this process is the intestinal immune system, which populates both the lamina propria and the epithelium. Reciprocal interaction between immune cells and the epithelium is of paramount importance as improperly regulated immune responses can result in inflammatory bowel disease (IBD), food allergies, and other immune-associated disorders [1][2][3]. Innate immune cells, including granulocytes and mast cells, are crucial components of this defense as they are often the first to respond to epithelial breach; however, the possible role for granulocytes in maintaining barrier integrity at later stages of immune responses remains unclear.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 258Daniel Sorobetea et al. Eur. J. Immunol. 2017. 47: 257-268 The murine-specific parasitic nematode Trichuris muris has been an invaluable tool to study intestinal immunity for nearly 50 years [4]. Once eggs are ingested, Trichuris-larvae hatch and burrow into the large-intestinal epithelium without penetrating the basal lamina, and remain in this niche unless expelled. Acute infections with T. muris are characterized by an early innate inflammatory response, accompanied by the induction of adaptive Th2 immunity and subsequent worm clearance [4]. After expulsion, the host immune system undergoes a complex and coordinated homeostatic event whereby inflammation is resolved and the infected tissue returns to steady state; a process characterized by immune contraction, clearance ...

Immunity to gastrointestinal nematode infections

“…Alternatively activated macrophages seem to increase in number after expulsion, 219 perhaps contributing to tissue repair, and there are dramatic changes to the epithelial niche, with increased numbers of mucosal mast cells that persist in the epithelium for months after expulsion and appear to affect epithelial barrier integrity. 220 However, other potential long-lasting consequences of acute T. muris infection remain unexplored. In contrast, H. polygyrus appears to be protective in several inflammatory models, 221,222 and this has been attributed to its ability to dampen inflammation by promoting the generation and function of regulatory T cells via some of its secreted proteins.…”

Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity?

“…In the recovery phase of the parasite infection, MCs slowly revert back to their initial protease phenotype and migrate from the jejunum to the draining LNs, blood, and finally to the spleen, thus restoring their physiologic number in the jejunal epithelium . At the opposite, a very recent issue from Sorobetea and co‐workers showed that acute Trichuris muris infection leads to MC accumulation in the epithelium of the large intestine and to persistence of mastocytosis beyond parasite expulsion . Interestingly, the different nature of the small and large intestine and the changes of the resident microbial communities were considered among the different hypothesis suggested by the authors to explain this disparity between the T. spiralis and the T. muris infection models.…”

Mastering gut permeability: New roles for old friends

“…Sorobetea et al show that activated mast cells persist in the gut after an acute infection of T. muris has been expelled, and remain there much longer than previously thought ( Fig. 1) [24]. Chronic infection, which is associated with a type 1 cytokine response, does not lead to the induction of persistent mast cells, demonstrating a role for type 2 cytokines in promoting mast cell accumulation.…”

“…Sorobetea et al. also rightly speculate regarding the impact of prolonged mastocytosis on the development of allergic and autoinflammatory conditions . Helminth infection has previously been associated with protection against development of autoimmune diseases such as IBD, but this new data would suggest the opposite may actually be true.…”

“…Continued production of MCPt-1 after expulsion may protect against secondary helminth infection via continued cleavage of cell-cell bonds, and it is likely that maintenance of a larger population of activated mast cells at the epithelium enables a rapid response to any pathogens that are able to gain entry into the lamina propria. Sorobetea et al also rightly speculate regarding the impact of prolonged mastocytosis on the development of allergic and autoinflammatory conditions [24]. Helminth infection has previously been associated with protection against development of autoimmune diseases such as IBD, but this new data would suggest the opposite may actually be true.…”