Myeloid PTEN promotes inflammation but impairs bactericidal activities during murine pneumococcal pneumonia.
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.
Schabbauer
Gernot
G
Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Austrian Academy of Sciences, Vienna, Austria. gernot.schabbauer@meduniwien.ac.at
Matt
Ulrich
U
Günzl
Philipp
P
Warszawska
Joanna
J
Furtner
Tanja
T
Hainzl
Eva
E
Elbau
Immanuel
I
Mesteri
Ildiko
I
Doninger
Bianca
B
Binder
Bernd R
BR
Knapp
Sylvia
S
D000818:Animals; D001770:Blood Bactericidal Activity / Q000276:immunology*; D045744:Cell Line, Tumor; D015169:Colony Count, Microbial; D015536:Down-Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011018:Pneumonia, Pneumococcal / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000276:immunology
D018836:Inflammation Mediators; D016753:Interleukin-10; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C487757:Pten protein, mouse