Loss of CD38 promotes severe allergic airway inflammation and hyperresponsiveness in mice.

Abstract

Cluster of differentiation 38 (CD38) is an enzyme that is expressed by immune cells and airway smooth muscle cells and is known to regulate nicotinamide adenine dinucleotide (NAD+) metabolism and inflammation. Studies have shown that CD38 increases airway hyperresponsiveness (AHR) in mice administered acute cytokine and allergen challenge, yet its role in chronic severe allergic airway inflammation is not known. In this study, we intranasally challenged wild-type (Cd38+/+) and homozygous Cd38 (Cd38-/-) knockout mice with phosphate-buffered saline (PBS) or mixed allergens (Alternaria alternata extract, Aspergillus fumigatus extract, Dermatophagoides pteronyssinus (house dust mite) extract, and ovalbumin) and bis-(3'-5')-cyclic dimeric guanosine monophosphate (MA+GMP) for four weeks. We measured AHR to methacholine using the flexiVent system, pro-inflammatory cytokine levels in bronchoalveolar lavage fluid by ELISA, and lung innate and adaptive immune cell populations by flow cytometry. Upon MA+GMP challenge, we observed that Cd38-/- mice have significantly higher AHR compared to Cd38+/+ mice. Interestingly, Cd38-/- mice challenged with MA+GMP had altered lung immune cell composition with greater type 2 innate lymphoid cells and eosinophils and less interferon-gamma producing natural killer cell populations compared to Cd38+/+ mice. These data suggest a key role for CD38 in negatively regulating type 2 inflammation, offering a novel role for CD38 in severe allergic inflammation.