We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis. Macrophages obtained as late as 45 days after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.
Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting l-arginine to l-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-κB-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors Nω-hydroxy-l-arginine or Nω-hydroxy-nor-l-arginine, but not by the iNOS inhibitor N-iminoethyl-l-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes l-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase II expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.
A detailed comparison of the oxidation of five compounds closely related to L-arginine (Arg) by purified recombinant neuronal and macrophage NO synthases (NOS I and NOS II) was performed. Homo-L-arginine (homo-Arg) is oxidized by both NOSs in the presence of NADPH with major formation of NO and homo-L-citrulline, with a molar ratio of close to 1, and minor formation of N omega-hydroxyhomo-L-arginine (homo-NOHA). Oxidation of homo-NOHA by the two NOSs also leads to NO and homocitrulline in a 1:1 molar ratio. On the contrary, N omega-hydroxynor-L-arginine (nor-NOHA) is a very poor substrate of NOS I and II, which fails to produce significant amounts of nitrite. The catalytic efficiency of both NOSs markedly decreases in the order Arg > NOHA > homo-Arg > homo-NOHA, as shown by the 20- and 10-fold decrease of kcat/Km observed for NOS I and NOS II, respectively, when comparing Arg to homo-NOHA. The greater loss of catalytic efficiency for homo-Arg, when compared to that for Arg, appears to occur at the first step (N-hydroxylation) of the reaction. In that regard, it is noteworthy that the Vm values for NOHA and homo-NOHA oxidation are very similar (about 1 and 2 micromol of NO min-1 mg of protein-1 for NOS I and II, respectively). In fact, lengthening of the Arg chain by one CH2 leads not only to markedly decreased kcat/Km but also to clear disturbances in NOS functioning. This is shown by a greater accumulation of the N omega-hydroxyguanidine intermediate (homo-NOHA:homocitrulline ratio between 0.2 and 0.4) and an increased consumption of NADPH for NO formation (between 2.0 and 2.6 mol of NADPH consumed for the formation of 1 mol of NO in the case of homo-Arg, instead of 1.5 mol in the case of Arg). Most of the above results could be interpreted by comparing the possible positionings of the various substrates relative to the two NOS active oxygen species which are believed to be responsible for the two steps of the reaction.
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