The NAD glycohydrolase CD38 regulates macrophage effector function and defense against Listeria monocytogenes. (INC7P.409)

Abstract

Abstract CD38, an ecto-enzyme with ADP-ribosyl cyclase activity, is expressed on myeloid cells and has been shown to be a regulator of innate immunity and inflammation. Our study aimed to determine whether CD38 plays a role in the immune response to the Gram-positive bacterial pathogen Listeria monocytogenes (Lm). Following an intravenous Lm infection, Cd38-/- mice exhibited increased mortality and morbidity compared to wild-type mice. Analysis of tissue homogenates showed greater bacterial burden in the spleen and liver of Cd38-/- mice 3-4 days post infection, suggesting that early Lm resistance is CD38-dependent. Bone marrow chimera experiments revealed that the increased susceptibility of Cd38-/- mice was due to defects on myeloid lineage cells. While recruitment of PMNs, CD11b+ cells and NK cells to the spleen was not affected in Lm-infected CD38-/- mice, the efflux of monocytes from the bone marrow to the blood and spleen was significantly reduced. Expression levels of IL-10, an inhibitor of macrophage effector function, were elevated in serum and spleens of Lm-infected Cd38-/- mice, and splenocytes isolated from Lm-infected Cd38-/- mice had decreased nitric oxide production and TNFα secretion. Furthermore, in vitro stimulation experiments showed decreased expression of key inflammatory cytokines in activated CD38-deficient macrophages. Our data suggest that CD38 deficiency impairs macrophage effector function that is crucial for an effective early immune response to Lm.