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J Immunol. 2017 Jun 1;198(11):4435-4447. doi: 10.4049/jimmunol.1601717. Epub 2017 May 1.

Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-β Synthesis Induced by Lipopolysaccharide.

Author information

1
Medical Scientist Training Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
2
Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
3
Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
4
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
5
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111.
6
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
7
Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
8
Center for Molecular Medicine, University of Cologne, 50674 Cologne, Germany.
9
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
10
Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
11
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426.
12
Department of Pediatric Critical Care Medicine, Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
13
Program in Innate Immunity, Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
14
Department of Bioengineering and Biology, Northeastern University, Boston, MA 02115; and.
15
Department of Molecular Biology and Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
16
Medical Scientist Training Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111; alexei.degterev@tufts.edu.

Abstract

The innate immune response is a central element of the initial defense against bacterial and viral pathogens. Macrophages are key innate immune cells that upon encountering pathogen-associated molecular patterns respond by producing cytokines, including IFN-β. In this study, we identify a novel role for RIPK1 and RIPK3, a pair of homologous serine/threonine kinases previously implicated in the regulation of necroptosis and pathologic tissue injury, in directing IFN-β production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-β synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-β production may be elicited in an analogous fashion using LPS in bone marrow-derived macrophages upon inhibition of caspases. Notably, this regulation requires kinase activities of both RIPK1 and RIPK3, but not the necroptosis effector protein, MLKL. Mechanistically, we provide evidence that necrosome-like RIPK1 and RIPK3 aggregates facilitate canonical TRIF-dependent IFN-β production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-β is markedly induced by avirulent strains of Gram-negative bacteria, Yersinia and Klebsiella, and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-β during the host inflammatory responses to bacterial infection and suggest that the axis in which these kinases operate may represent a target for bacterial virulence factors.

PMID:
28461567
PMCID:
PMC5471631
DOI:
10.4049/jimmunol.1601717
[Indexed for MEDLINE]
Free PMC Article

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