Acidic Mammalian Chitinase Is Not a Critical Target for Allergic Airway Disease

Fitz, Lori; DeClercq, Charlene; Brooks, Jonathan; Kuang, Wenjun; Bates, Brian; Demers, Delia; Winkler, Aaron; Nocka, Karl; Jiao, Aiping; Greco, Rita; Mason, Lawrence E.; Fleming, Margaret; Quazi, Amira; Wright, Jill F.; Goldman, Samuel J.; Hubeau, Cédric; Williams, Cara

doi:10.1165/rcmb.2011-0095oc

Cited by 33 publications

(43 citation statements)

References 35 publications

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“…It has been reported that AMCase-deficient mice did not show dramatic defects after sensitization and challenge with OVA or HDM plus cockroach allergen (39). These results seem to conflict with our observations.…”

Section: Discussioncontrasting

confidence: 99%

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

Kim¹,

Morita²,

Kobayashi³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Discussioncontrasting

confidence: 99%

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

Kim¹,

Morita²,

Kobayashi³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…While we do not observe an increase in overall HDM uptake by pulmonary DCs following blockade of PD-L2 in vivo , it is possible that PD-L2 blockade may subtly regulate the ability of DCs to take up or present specific allergenic peptides. In primary murine tracheal epithelial cells, IL-12 also inhibited the IL-13-induced expression of the genes encoding IL-33, (a Th2-inducing cytokine 45-46 ), AMCase (capable of enhancing allergen-driven IL-13 production 47-48 ), and Fizz1 (capable of inducing airway eosinophilia and airway remodeling 49 ). We also see reduced IL-13-driven expression of Sprr2b following IL-12 treatment.…”

Section: Discussionmentioning

confidence: 99%

PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production

et al. 2013

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Studies examining the role of PD-L2/PD-1 in asthma have yielded conflicting results. To clarify its role, we examined PD-L2 expression in biopsies from human asthmatics and lungs of aeroallergen-treated mice. PD-L2 expression in bronchial biopsies correlated with the severity of asthma. In mice, allergen exposure increased PD-L2 expression on pulmonary myeloid dendritic cells, and PD-L2 blockade diminished allergen-induced airway hyperresponsiveness (AHR). In contrast, PD-1 blockade had no impact, suggesting that PD-L2 promotes AHR in a PD-1-independent manner. Decreased AHR was associated with enhanced serum IL-12 p40 and in vitro stimulation of DCs with allergen and PD-L2-Fc reduced IL-12 p70 production, suggesting that PD-L2 inhibits allergen-driven IL-12 production. In our model, IL-12 did not diminish Th2 responses, but rather directly antagonized IL-13-inducible gene expression, highlighting a novel role for IL-12 in regulation of IL-13 signaling. Thus, allergen-driven enhancement of PD-L2 signaling through a PD-1-independent mechanism limits IL-12 secretion, exacerbating AHR.

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“…Age-matched 10-to 14-wk-old female BALB/c mice received a single intratracheal instillation of saline or 100 mg of house dust mite (HDM) extract from Dermatophagoides pteronyssinus (Greer Laboratories, Lenoir, NC) resuspended in saline using a 100-ml Hamilton glass syringe, as previously described (29). Animals were dosed by oral gavage with saline (vehicle), 2 mg/kg dexamethasone (Dex) USP (Sigma-Aldrich), or 200 mg/kg CP-456,773, twice daily, on the day before and the day of HDM challenge.…”

Section: Murine Model Of Acute House Dust Mite Challengementioning

confidence: 99%

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Primiano

Lefker

Bowman

et al. 2016

The Journal of Immunology

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137

117

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A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains–containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro–IL-1β and pro–IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome–selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream–induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

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Acidic Mammalian Chitinase Is Not a Critical Target for Allergic Airway Disease

Cited by 33 publications

References 35 publications

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

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

PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

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