| First Author | Saleh D | Year | 2017 |
| Journal | J Immunol | Volume | 198 |
| Issue | 11 | Pages | 4435-4447 |
| PubMed ID | 28461567 | Mgi Jnum | J:247747 |
| Mgi Id | MGI:5926880 | Doi | 10.4049/jimmunol.1601717 |
| Citation | Saleh D, et al. (2017) Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-beta Synthesis Induced by Lipopolysaccharide. J Immunol 198(11):4435-4447 |
| abstractText | 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-beta. 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-beta production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-beta synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-beta 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-beta production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-beta 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-beta 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. |
