Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

J Immunol. 2015 Sep 15;195(6):2612-23. doi: 10.4049/jimmunol.1402944. Epub 2015 Aug 3.

Abstract

Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor-induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b(+) conventional DCs (cDCs), CD8(+) cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow-derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP(+/-) macrophages. Additionally, the increased activation in c-FLIP-deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents
  • Antigen Presentation / immunology
  • Apoptosis / immunology
  • B7-1 Antigen / biosynthesis
  • B7-2 Antigen / biosynthesis
  • Bone Marrow Cells / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / immunology*
  • Caspase 8 / genetics
  • Caspase 8 / immunology*
  • Dendritic Cells / immunology*
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Granulocyte Colony-Stimulating Factor / biosynthesis
  • Histocompatibility Antigens Class II / biosynthesis
  • Inflammation / immunology
  • Interleukin-2 / biosynthesis
  • Lectins, C-Type / immunology
  • Leukocyte Count
  • Mice
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology*
  • Neutrophils / cytology
  • Neutrophils / immunology
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / immunology
  • Splenomegaly / immunology
  • T-Lymphocytes / immunology
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 4 / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • B7-1 Antigen
  • B7-2 Antigen
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cd86 protein, mouse
  • Cflar protein, mouse
  • Histocompatibility Antigens Class II
  • Interleukin-2
  • Lectins, C-Type
  • RNA, Small Interfering
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • dectin 1
  • Granulocyte Colony-Stimulating Factor
  • p38 Mitogen-Activated Protein Kinases
  • Casp8 protein, mouse
  • Caspase 8