Pathogen-induced apoptotic neutrophils express heat shock proteins and elicit activation of human macrophages.
Ingestion of aged or irradiated apoptotic neutrophils actively suppresses stimulation of macrophages (Mphi). Many bacterial pathogens can also provoke apoptosis in neutrophils, but little is known about how such apoptotic cells influence Mphi activation. We found that neutrophils undergoing apoptosis induced by UV irradiation, Escherichia coli, or Staphylococcus aureus could either stimulate or inhibit Mphi activation. In contrast to Mphi that had ingested irradiated apoptotic neutrophils, Mphi that had phagocytosed bacteria-induced apoptotic neutrophils exhibited markedly increased production of the proinflammatory cytokine TNF-alpha, but not the anti-inflammatory cytokine TGF-beta. Moreover, ingestion of bacteria, but not UV-induced apoptotic neutrophils, caused increased expression of FcgammaRI on Mphi, and this effect was not provoked directly by bacteria associated with the apoptotic neutrophils. Instead, we found that a link between pathogen-induced apoptotic neutrophils and up-regulation of the heat shock proteins HSP60 and HSP70, and we also observed that recombinant HSP60 and HSP70 potentiated LPS-stimulated production of TNF-alpha in Mphi. The opposing macrophage responses to neutrophils undergoing apoptosis induced in different ways may represent a novel mechanism that regulates the extent of the immune response to invading microbes in two steps: first by aiding the functions of Mphi at an early stage of infection, and subsequently by deactivating those cells through removal of uninfected apoptotic neutrophils. HSP induction in neutrophils may provide the danger signals required to generate a more effective macrophage response.
Zheng
Limin
L
Key Laboratory of Gene Engineering of the Education Ministry, Department of Biochemistry, College of Life Sciences, Sun Yatsen (Zhongshan) University, Guangzhou 510 275, People's Republic of China. ls110@zsu.edu.cn
He
Min
M
Long
Min
M
Blomgran
Robert
R
Stendahl
Olle
O
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018834:Chaperonin 60 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D017452:Receptors, IgG / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D017452:Receptors, IgG; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide