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

Significance Millions of people are affected by asthma and that number is growing. A clear understanding of how the disease develops is lacking. The immune responses to inhaled allergens like house dust mite (HDM) provide much of the basis of asthma. Acidic mammalian chitinase (AMCase) is an enzyme that degrades chitin, a major structural polymer in the exoskeleton of HDM. By the use of a newly generated enzymatically dead AMCase knockin mouse, we found that AMCase enzymatic activity is of critical importance in the control of type 2 immune responses to inhaled HDM. This discovery may help the understanding of the mechanisms that govern the development of chitin-related asthma and allergy and may lead to new therapeutic strategies in these disorders. 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.