Constitutively active autophagy in macrophages dampens inflammation through metabolic and post-transcriptional regulation of cytokine production
Jinjin Xu,
Lingjia Kong,
Blayne A. Oliver,
Bihua Li,
Elizabeth A. Creasey,
Gaelen Guzman,
Monica Schenone,
Kimberly L. Carey,
Steven A. Carr,
Daniel B. Graham,
Jacques Deguine,
Ramnik J. Xavier
Affiliations
Jinjin Xu
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Lingjia Kong
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Blayne A. Oliver
Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Bihua Li
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Elizabeth A. Creasey
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Gaelen Guzman
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Monica Schenone
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Kimberly L. Carey
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Steven A. Carr
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Daniel B. Graham
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Jacques Deguine
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ramnik J. Xavier
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Corresponding author
Summary: Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.
