Format

Send to

Choose Destination
J Allergy Clin Immunol. 2019 Dec 11. pii: S0091-6749(19)31637-9. doi: 10.1016/j.jaci.2019.11.041. [Epub ahead of print]

Non-canonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure.

Author information

1
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
2
Department of Dermatology, Duke University, Durham, NC 27710, USA.
3
Knockout Mouse Core Laboratory, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
4
Molecular Genomics Core Laboratory, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
5
Duke Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27708, USA.
6
Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina, USA.
7
Division of Intramural Research, 111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
8
Comparative Medicine Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
9
Department of Dermatology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
10
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Electronic address: jennifer.martinez3@nih.gov.

Abstract

BACKGROUND:

Control of the inflammatory response is critical to maintaining homeostasis, and failure to do so contributes to the burden of chronic inflammation associated with several disease states. The mechanisms that underlie immunosuppression, however, remain largely unknown. While defects in autophagy machinery have been associated with inflammatory pathologies, we now appreciate that autophagic components participate in non-canonical pathways distinct from classical autophagy. We have previously demonstrated that LC3-associated phagocytosis (LAP), a non-canonical autophagic process dependent on Rubicon (RUBCN), contributes to immunosuppression.

OBJECTIVE:

We used Rubcn-/- mice to examine the role of in mediating the UV-induced immunotolerant program in a model of contact hypersensitivity (CHS).

METHODS:

Flow cytometry and transcriptional analysis was used to measure immune cell infiltration and activation in the skin of Rubcn+/+ and Rubcn-/- mice during the CHS response.

RESULTS:

Here, we demonstrate that LAP is required for UV-induced immunosuppression, and UV exposure induces a broadly anti-inflammatory transcriptional program dependent on Rubicon. Rubcn-/- mice are resistant to UV-induced immunosuppression and instead display exaggerated inflammation in a model of contact hypersensitivity (CHS). Specifically, RUBCN deficiency in CD301b+ dermal dendritic cells (dDC2s) results in their increased antigen presentation capacity and subsequent hyperactivation of the CD8+ T cell response.

CONCLUSIONS:

LAP functions to limit the immune response and is critical in maintaining the balance between homeostasis and inflammation.

KEYWORDS:

LAP; Rubicon; antigen presentation; autophagy; contact hypersensitivity; dendritic cells; efferocytosis; inflammation

PMID:
31837371
DOI:
10.1016/j.jaci.2019.11.041
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center