AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

Abstract

Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33. These data suggest that AMCase is a crucial regulator of type 2 immune responses to inhaled chitin-containing aeroallergens.AMCase | chitin | house dust mite | IL-33

Acidic chitinase primes the protective immune response to gastrointestinal nematodes

“…Still, additional reports have proposed that AMCase has a protective role. One showed that the type 2 inflammatory response following chitin challenge was ameliorated in mice overexpressing AMCase 8 , and another observed increased allergic lung disease in mice specifically lacking AMCase enzymatic activity 11 . The contrasting functional implications of AMCase highlighted in these studies have yet to be fully reconciled.…”

Epithelial Cell Regulation of Allergic Diseases

“…Consistent with the concept that chitin must be enzymatically broken down to avoid aberrant type 2 responses, mice deficient in the enzymatically active AMCase (AMCase-ED) have an exacerbated allergic airway inflammation in response to house dust mite (HDM) extract [11•]. Bone-marrow chimera studies showed that AMCase in structural cells, more so than hematopoeitically expressed (macrophage) AMCase, is central in mediating enhanced IL-33 and eosionophilia following allergen exposure [11•].…”

“…Bone-marrow chimera studies showed that AMCase in structural cells, more so than hematopoeitically expressed (macrophage) AMCase, is central in mediating enhanced IL-33 and eosionophilia following allergen exposure [11•]. Specifically, administration of chitin in the airways of mice leads to eosinophilia and mucus production.…”

“…Surprisingly, only large-sized chitin could induce IL-33 in the BAL, which was more pronounced in AMCase-ED mice but small size could not. 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. 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•]. However, the role of chitotriosidase CHIT1 is yet to be explored in the context of allergic diseases.…”