Bacteria induce prolonged PMN survival via a phosphatidylcholine-specific phospholipase C- and protein kinase C-dependent mechanism.
Polymorphonuclear leukocytes (PMNs) are essential for the human innate immune defense, limiting expansion of invading microorganisms. PMN turnover is controlled by apoptosis, but the regulating signaling pathways remain elusive, largely due to inherent differences between mice and humans that undermine use of mouse models for understanding human PMN biology. Here, we aim to elucidate signal transduction mediating survival of human peripheral blood PMNs in response to bacteria, such as Yersinia pseudotuberculosis, an enteropathogen that causes the gastro-intestinal disease yersiniosis, as well as Escherichia coli and Staphylococcus aureus. Determinations of cell death reveal that uninfected control cells undergo apoptosis, while PMNs infected with either Gram-positive or -negative bacteria show profoundly increased survival. Infected cells exhibit decreased caspase 3 and 8 activities, increased mitochondrial integrity and are resistant to apoptosis induced by a death receptor ligand. This bacteria-induced response is accompanied by pro-inflammatory cytokine production including interleukin-8 and tumor necrosis factor-α competent to attract additional PMNs. Using agonists and pharmacological inhibitors, we show participation of Toll-like receptor 2 and 4, and interestingly, that protein kinase C (PKC) and phosphatidylcholine-specific phospholipase C (PC-PLC), but not tyrosine kinases or phosphatidylinositol-specific phospholipase C (PI-PLC) are key players in this dual PMN response. Our findings indicate the importance of prolonged PMN survival in response to bacteria, where general signaling pathways ensure complete exploitation of PMN anti-microbial capacity.
Department of Molecular Biology, Umeå Centre for Microbial Research (UCMR), Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå Sweden.
Saskia F
SF
Erttmann
Department of Molecular Biology, Umeå Centre for Microbial Research (UCMR), Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå Sweden.
Nelson O
NO
Gekara
Department of Molecular Biology, Umeå Centre for Microbial Research (UCMR), Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå Sweden.
Maria
M
Fällman
D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D053181:Caspase 8 / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011493:Protein Kinase C / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D010738:Type C Phospholipases / Q000276:immunology* / Q000378:metabolism
C508606:CXCL8 protein, human; D016209:Interleukin-8; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D010738:Type C Phospholipases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8