Autophagy and Inflammasome activation triggered by LPS-negative Ehrlichia is dependent on both mTOR activation and MyD88 signaling
| Autor: | Jennie Vorhauer, Mounia Alaoui-El-Azher, Alan Wells, Nahed Ismail |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 196:62.12-62.12 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.196.supp.62.12 |
| Popis: | Lipopolysaccharide (LPS) positive pathogens trigger autophagy and inflammasome activation. Autophagy is an innate anti-microbial host defense that maintains tissue homeostasis and is regulated by the nutrient-sensing mTORC1 complex. However it is unknown how the LPS-negative, Gram negative Ehrlichia elicits the same response. Monocytic Ehrlichia triggers Type I IFN-dependent NLRP3 inflammasome activation, which detrimentally effects host response to Ehrlichia. In this study, we examined the regulatory mechanisms of autophagy and inflammasome activation. With toll like receptor (TLR)-adaptor molecule MYD88 deficient mice, we reveal a crucial role for MYD88 in mediation of Ehrlichia-dependent inflammasome activation and hepatic inflammation. This role is demonstrated by decreased Caspase 1 and IL-1β levels in infected liver tissues, and decreased inflammatory cytokines (TNF-α and IL-6) when compared to wild type. Ehrlichia-induced inflammasome activation in wild type mice correlated with inhibition of autophagy. Ehrlichia-induced inhibition of autophagy in infected macrophages was dependent on TLR9, TLR2, and their adaptor MYD88. Inhibition was enhanced by IFN-β stimulation. We also demonstrate that mTORC1 autophagy inhibition acts downstream of MYD88. These data suggest that LPS-negative Ehrlichia inhibit autophagy and activate the inflammasome through mTORC1 activation and MYD88 signaling, contributing to Ehrlichia-induced inflammatory disregulation and liver injury. |
| Databáze: | OpenAIRE |
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