ABSTRACT
Resolution of inflammation is an important hallmark in the course of infectious diseases. Dysregulated inflammatory responses may have detrimental consequences for the affected organism. Therefore, tight regulation of inflammation is indispensable. Among numerous modulatory signaling pathways, the PI3K/PTEN signaling pathway has been proposed recently to be involved in the regulation of innate immune reactions. Here, we attempted to elucidate molecular mechanisms that contribute to the modulatory properties of the PI3K signaling pathway in inflammation. PTEN-deficient macrophages, which harbor constitutively active PI3Ks, were analyzed in response to gram-negative bacteria and PAMPs such as LPS. PTEN-deficient cells showed reduced inflammatory cytokine production, which was accompanied by reduced MAPK signaling activation in early- as well as late-phase activation. Simultaneously, we found increased levels of the MKP DUSP1, as well as the anti-inflammatory cytokine IL-10. Our data suggest that differential DUSP1 regulation coupled with enhanced IL-10 production contributes to the anti-inflammatory properties of the PI3K pathway.
Subject(s)
Dual Specificity Phosphatase 1/physiology , Inflammation/prevention & control , Interleukin-10/physiology , Phosphatidylinositol 3-Kinases/physiology , Signal Transduction/physiology , Acinetobacter baumannii/immunology , Animals , Dual Specificity Phosphatase 1/genetics , MAP Kinase Signaling System , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , PTEN Phosphohydrolase/physiology , RNA, Messenger/analysis , Toll-Like Receptors/physiologyABSTRACT
Phosphatidylinositol 3-kinase has been described as an essential signaling component involved in the chemotactic cell influx that is required to eliminate pathogens. At the same time, PI3K was reported to modulate the immune response, thus limiting the magnitude of acute inflammation. The precise role of the PI3K pathway and its endogenous antagonist phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during clinically relevant bacterial infections is still poorly understood. Utilizing mice lacking myeloid cell-specific PTEN, we studied the impact of PTEN on the immune response to Streptococcus pneumoniae. Survival analysis disclosed that PTEN-deficient mice displayed less severe signs of disease and prolonged survival. The inflammatory response to S. pneumoniae was greatly reduced in macrophages in vitro and in vivo. Unexpectedly, neutrophil influx to the lungs was significantly impaired in animals lacking myeloid-cell PTEN, whereas the additional observation of improved phagocytosis by alveolar macrophages lacking PTEN ultimately resulted in unaltered lung CFUs following bacterial infection. Together, the absence of myeloid cell-associated PTEN and consecutively enhanced PI3K activity dampened pulmonary inflammation, reduced neutrophil influx, and augmented phagocytic properties of macrophages, which ultimately resulted in decreased tissue injury and improved survival during murine pneumococcal pneumonia.
Subject(s)
Blood Bactericidal Activity/immunology , Inflammation Mediators/physiology , Myeloid Cells/enzymology , PTEN Phosphohydrolase/physiology , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/microbiology , Animals , Cell Line, Tumor , Colony Count, Microbial , Down-Regulation/immunology , Interleukin-10/physiology , Macrophages, Alveolar/enzymology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/microbiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myeloid Cells/pathology , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/biosynthesis , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors , Pneumonia, Pneumococcal/enzymology , Pneumonia, Pneumococcal/pathology , Streptococcus pneumoniae/growth & development , Streptococcus pneumoniae/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Up-Regulation/immunologyABSTRACT
The role of the PI3-kinase pathway and its antagonist PTEN in the regulation of innate immune responses has only recently attracted the attention of the scientific community. The PI3K/PTEN signaling axis is most renowned for its critical involvement in the malignant transformation of cells leading to tumorigenesis. PI3K function in the regulation of innate immunity, either pro-inflammatory or anti-inflammatory, is still a controversial issue. Undoubtedly, PI3K serves as an essential pro-inflammatory signaling molecule to activate leukocytes, initiate migration and facilitate phagocytosis. Nevertheless, it is less clear how PI3K and PTEN modulate the amplitude of immune responses. Here, we review recent advances on the immune biology by means of reverse genetics analyzing the role of the PI3K/PTEN signaling cascade in innate immunity.
