Acidic chitinase primes the protective immune response to gastrointestinal nematodes

Abstract

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103+ dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

Epithelial Cell Regulation of Allergic Diseases

“…These findings are in contrast to another report demonstrating a lack of effect in AMCase KO mice in the allergic phenotype in either acute or chronic model of dust mite exposure [12]. The mechanism behind these differences are unclear but may involve the fact that one study used an intact but enzymatically inactive AMCase that can still bind chitin [8], versus one in which AMCase protein expression was abolished [12], thus suggesting that while AMCase’s best-known function is to cleave chitin, it may play other roles in chitin biology. Moreover, it is possible that the other active chitinase, chitotriosidase ( CHIT1 ), has a redundant role in the absence of AMCase; its expression was reportedly detected in the lungs of AMCase KO mice [12] but not in AMCase-ED mice [11•].…”

“…The authors claimed that chitin or chitin-containing dust mite extracts activates caspase-1 which in turn activates caspase-7 which then cleaves and inactivates IL-33 thus leading to resolution of type 2 inflammation [11•]. These findings are in contrast to another report demonstrating a lack of effect in AMCase KO mice in the allergic phenotype in either acute or chronic model of dust mite exposure [12]. The mechanism behind these differences are unclear but may involve the fact that one study used an intact but enzymatically inactive AMCase that can still bind chitin [8], versus one in which AMCase protein expression was abolished [12], thus suggesting that while AMCase’s best-known function is to cleave chitin, it may play other roles in chitin biology.…”

Acidic mammalian chitinase is a proteases-resistant glycosidase in mouse digestive system

“…Recently, AMCase has been shown to have a critical role in initiating type 2 immunity against the chitin-containing nematode18. Thus, AMCase can function as not only a digestive enzyme but also a part of the host defense against chitin-containing pathogens in the mouse GIT.…”

“…AMCase is an important downstream effector of interleukin-13 stimulation in T Helper-2 (Th2) cell-mediated immune responses to ovalbumin, pathogens and parasites917. AMCase also functions as a critical initiator of protective type 2 responses to intestinal nematodes18. In addition, several genetic variants of AMCase are associated with bronchial asthma in humans19202122.…”

Immunity to gastrointestinal nematode infections

“…Chitin elicits strong type 2 immunity in the lung mucosa, 18,19 and acidic mammalian chitinase, which is predominantly expressed by certain pulmonary 20 and gastrointestinal 21 epithelial cells, is required for optimal protection against both N. brasiliensis and H. polygyrus infections. 22 However, as chitin is also a major part of the fungal cell wall, it alone is an insufficient explanation for the induction of antiparasitic immunity. Given that intestinal nematodes tend to cause more tissue destruction than other pathogens (because of their sheer size and invasiveness), it is perhaps more plausible that type 2 immunity results from combined recognition of both endogenous damage-associated alarmins and worm-derived molecules that become available for uptake after larval molting (including chitin), as well as parasite-derived antigens that are continuously secreted throughout infection.…”