Although numerous studies have investigated the outcome of exogen

Although numerous studies have investigated the outcome of exogenous or endogenous IL-10 on a variety of infectious and inflammatory animal models, surprisingly few studies have directly addressed if and how IL-10 influences neutrophil responsiveness in vivo or ex vivo. Most in vivo studies, in fact, have overlooked the effects Gamma-secretase inhibitor of IL-10 in different models of inflammation-driven pathologies, including adjuvant- or crystal-induced arthritis 63, 64, zymosan-induced peritoneal inflammation

65, LPS-induced or IgG immune complex-induced acute lung injury 66–68, bacterial or fungal infections 69–71, myocardial- 72, hepatic- 73 or visceral- 74, 75 dependent ischemia-reperfusion injuries, BSA-induced delayed type of hypersensitivity 76, OVA-induced model of asthma 77 and hemorrhagic shock 78. Independent of the type or cause of injury, in all of these studies exogenous IL-10 (or IL-10 gene transfer) effectively reduced the severity of local or PLX3397 datasheet systemic inflammation, mainly by blocking cell trafficking, in particular the early influx of neutrophils to the injury site. The reduced accumulation of neutrophils in inflamed organs was ascribed to an IL-10-mediated inhibition of macrophage- or tissue-derived neutrophil chemoattractants 63–68 or, in a single instance, to an IL-10-mediated

increase in neutrophil apoptosis via unidentified mechanisms 79. Conversely, the exacerbated inflammatory reactions occurring in IL-10−/− mice following acute Akt inhibitor lung inflammation triggered by LPS 80, zymosan-induced

peritonitis 81 or liver injury 82, correlated with increased production of neutrophil chemoattractants and with augmented neutrophil infiltration at inflammatory sites. Additional evidence that IL-10 keeps inflammation under control in vivo by selectively inhibiting the recruitment of neutrophils derives from neutrophil depletion experiments performed in IL-10−/− mice; the combination of a lack of IL-10 and neutrophils decreased the severity of gastritis in Helicobacter felis-infected mice 83. Similarly, mice carrying neutrophil- and macrophage-specific conditional IL-10R1 gene targeting displayed increased sensitivity to LPS in an IL-10-dependent LPS model of endotoxemia 84; a result resembling that described in IL-10−/− mice 80–82 and, additionally, providing supporting for the crucial role of neutrophils (and macrophages) as direct IL-10 cellular targets in vivo. Interestingly, in a recent article, neutrophils were shown to play an important regulatory role during various murine microbial infections in vivo by secreting IL-10 85. In the same study, the authors mention (data not shown) that monocytes, but not neutrophils, from IL-10−/− mice showed a tenfold increase in the production of pro-inflammatory cytokines in response to BCG, indicating that (at least in mice) an autocrine IL-10 regulatory loop controls the monocyte response but does not inhibit pro-inflammatory cytokine production by neutrophils 85.

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