Reduced antilisterial activity of TNF-deficient bone marrow-derived macrophages is due to impaired superoxide production

Abstract

Mice deficient for TNF ligand and receptor type 1 have demonstrated the importance of TNF in the host defense against Listeria monocytogenes. To investigate the particular deficiency of macrophages derived from TNF/lymphotoxin (LT)‐α− / − mice in antilisterial growth control, bone marrow‐derived macrophages (BMDM) were used for in vitro infection experiments. After the combined treatment with IFN‐γ and lipopolysaccharide (LPS), production of NO by wild‐type (wt) and TNF/LT‐α− / − BMDM was induced to comparable levels, but only wt BMDM controlled L. monocytogenes growth efficiently. Nevertheless, inhibition of NO production led to a remarkable loss of antilisterial activity. This suggests that presence of NO is necessary but not sufficient for L. monocytogenes killing and that elimination of L. monocytogenes requires additional effector molecules. The LPS‐inducible superoxide production of TNF/LT‐α− / − BMDM was impaired. Accordingly both scavenging of superoxide and peroxynitrite led to reduced L. monocytogenes killing by wt BMDM. In addition, peroxynitrite was able to kill L. monocytogenes in vitro. Together these findings suggest that the defective host defense of TNF/LT‐α‐deficient mice against L. monocytogenes partially stems from reduced superoxide production of macrophages due to the absence of TNF and imply a function for peroxynitrite, the reaction product of NO and superoxide, in the intracellular killing of L. monocytogenes.

α-Galactosylceramide Promotes Killing ofListeria monocytogeneswithin the Macrophage Phagosome through Invariant NKT-Cell Activation

“…NO does not play a major role in enhanced bactericidal activity of M by ␣-GalCer treatment. NO is produced by M after L. monocytogenes infection and plays a crucial role in intracellular killing of L. monocytogenes (48,52,69,71). Moreover, NO production is induced by IFN-␥ (4, 7, 38, 48).…”

“…ROI are produced by M in response to L. monocytogenes infection, and they play a central role in listerial killing within phagosomes (52,53,59). To determine the role of ROI experimentally, the respiratory bursts in M from ␣-GalCer-and vehicle-treated C57BL/6 mice were compared.…”

The Host Resistance Locussst1Controls Innate Immunity toListeria monocytogenesInfection in Immunodeficient Mice

“…These cytokines can also enhance the resistance to the pathogen when administered before infection (48), and their blockade increased the growth of bacteria (49). The mechanisms by which these cytokines modulate the growth of L. monocytogenes involve the production of toxic compounds, such as ROI, NO, and peroxynitrite (50). The mechanism of the sst1-mediated control of host resistance to L. monocytogenes appeared to be IFN-␥-dependent, but NO-independent, because only treatment with scavengers of ROI (NAC and SOD) significantly increased bacterial multiplication in the resistant macrophages, whereas inhibition of NO production had no effect on sst1 function.…”

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection

“…This observation indicates that intracellular signaling pathways of the different receptors converge upstream of MK2. Following uptake by cytokine-activated macrophages, bacteria in the phagolysosome are confronted with a battery of microbicidal substances such as reactive oxygen and nitrogen species (37,39,40). Evidence has been provided that generation of NO is an essential host mechanism in antilisterial defense because inhibition of iNOS increases bacterial load and susceptibility of mice to L. monocytogenes infection (40).…”