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Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota

Nature Microbiologyvolume 3pages11311141 (2018) | Download Citation


As a conserved pathway that lies at the intersection between host defence and cellular homeostasis, autophagy serves as a rheostat for immune reactions. In particular, autophagy suppresses excess type I interferon (IFN-I) production in response to viral nucleic acids. It is unknown how this function of autophagy relates to the intestinal barrier where host–microbe interactions are pervasive and perpetual. Here, we demonstrate that mice deficient in autophagy proteins are protected from the intestinal bacterial pathogen Citrobacter rodentium in a manner dependent on IFN-I signalling and nucleic acid sensing pathways. Enhanced IFN-stimulated gene expression in intestinal tissue of autophagy-deficient mice in the absence of infection was mediated by the gut microbiota. Additionally, monocytes infiltrating into the autophagy-deficient intestinal microenvironment displayed an enhanced inflammatory profile and were necessary for protection against C. rodentium. Finally, we demonstrate that the microbiota-dependent IFN-I production that occurs in the autophagy-deficient host also protects against chemical injury of the intestine. Thus, autophagy proteins prevent a spontaneous IFN-I response to microbiota that is beneficial in the presence of infectious and non-infectious intestinal hazards. These results identify a role for autophagy proteins in controlling the magnitude of IFN-I signalling at the intestinal barrier.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request. FASTQ files corresponding to the RNA–seq data have been deposited in a public database (RNA–seq GEO accession no. GSE115025, 16S GEO accession no. GSE116491).

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The authors acknowledge the following NYU facilities for use of their instruments and technical assistance: the Microscopy Core (RR023704), the Histopathology and Immunohistochemistry Core (P30CA016087, NIH S10 OD010584-01A1 and S10 OD018338-01), the Cytometry and Cell Sorting Laboratory (P30CA016087), the Genome Technology Center (P30CA016087) and the Gnotobiotic Facility (Colton Center for Autoimmunity). This work was supported by US National Institute of Health (NIH) grants R01 HL123340 (K.C.), R01 DK093668 (K.C.), R01 DK103788 (K.C.), R01 AI121244 (K.C.), F31 DK111139 (P.K.M.) and T32 AI100853 (E.R.), a Faculty Scholar grant from the Howard Hughes Medical Institute (K.C.), an Advanced Research Grant from the Merieux Institute (K.C.), a Rainin Foundation Innovator Award (K.C.), the Stony Wold-Herbert Fund (K.C.) and philanthropy from B. Levine (K.C.), and a Crohn’s & Colitis Foundation Research Fellowship Award (A.M.). K.C. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.

Author information


  1. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, USA

    • Patricia K. Martin
    • , Amanda Marchiando
    • , Eugene Rudensky
    • , Frank Yeung
    • , Samantha L. Schuster
    • , Elisabeth Kernbauer
    •  & Ken Cadwell
  2. Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY, USA

    • Patricia K. Martin
    • , Eugene Rudensky
    •  & Frank Yeung
  3. Department of Pathology, New York University School of Medicine, New York, NY, USA

    • Ruliang Xu
  4. Department of Microbiology, New York University School of Medicine, New York, NY, USA

    • Ken Cadwell


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P.K.M., A.M. and K.C. formulated the original hypothesis, designed the study and analysed the results. E.R. assisted with transcriptomics analyses. R.X. performed histopathology analyses. E.K. assisted with experiments involving GF mice. S.L.S. and F.Y. assisted with analyses of microbial communities. P.K.M. and K.C. wrote the manuscript, and all authors commented on the manuscript, data and conclusions.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Ken Cadwell.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–6.

  2. Reporting Summary

  3. Supplementary Table 1

    Gene expression dataset, related to Fig. 6. Shown are normalized log2 expression values for 812 altered genes from infiltrating inflammatory monocytes isolated from the colon of day 9 C. rodentium-infected WT and Atg16L1HM mice.

  4. Supplementary Table 2

    A dataset showing the exact P value for all graphs in this manuscript.

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