Payel Sil1, Jutamas Suwanpradid2, Ginger Muse1, Artiom Gruzdev3, Liwen Liu4, David L Corcoran5, Cynthia J Willson6, Kyathanahalli Janardhan6, Sara Grimm7, Page Myers8, Laura Miller Degraff1, Amanda S MacLeod9, Jennifer Martinez10. 1. Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 2. Department of Dermatology, Duke University, Durham, NC. 3. Knockout Mouse Core Laboratory, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 4. Molecular Genomics Core Laboratory, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 5. Duke Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC. 6. Integrated Laboratory Systems, Inc, Research Triangle Park, NC. 7. Division of Intramural Research, Research Triangle Park, NC. 8. Comparative Medicine Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 9. Department of Dermatology, Duke University, Durham, NC; Department of Immunology, Duke University, Durham, NC; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC. 10. Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. 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. Although defects in autophagy machinery have been associated with inflammatory pathologic conditions, we now appreciate that autophagic components participate in noncanonical pathways distinct from classical autophagy. We have previously demonstrated that LC3-associated phagocytosis (LAP), a noncanonical autophagic process dependent on Rubicon (rubicon autophagy regulator [RUBCN]), contributes to immunosuppression. OBJECTIVE: We used Rubcn-/- mice to examine the role of the LAP pathway in mediating the UV-induced immunotolerant program in a model of contact hypersensitivity (CHS). METHODS: Flow cytometry and transcriptional analysis were 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 that 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 CHS. Specifically, RUBCN deficiency in CD301b+ dermal dendritic cells 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. Published by Elsevier Inc.
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. Although defects in autophagy machinery have been associated with inflammatory pathologic conditions, we now appreciate that autophagic components participate in noncanonical pathways distinct from classical autophagy. We have previously demonstrated that LC3-associated phagocytosis (LAP), a noncanonical autophagic process dependent on Rubicon (rubicon autophagy regulator [RUBCN]), contributes to immunosuppression. OBJECTIVE: We used Rubcn-/- mice to examine the role of the LAP pathway in mediating the UV-induced immunotolerant program in a model of contact hypersensitivity (CHS). METHODS: Flow cytometry and transcriptional analysis were 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 that 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 CHS. Specifically, RUBCN deficiency in CD301b+ dermal dendritic cells 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. Published by Elsevier Inc.
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Authors: Vivian Lei; Chelsea Handfield; Jeffery T Kwock; Stephen J Kirchner; Min Jin Lee; Margaret Coates; Kaiyuan Wang; Qingjian Han; Zilong Wang; Jennifer G Powers; Sarah Wolfe; David L Corcoran; Brian Fanelli; Manoj Dadlani; Ru-Rong Ji; Jennifer Y Zhang; Amanda S MacLeod Journal: J Invest Dermatol Date: 2022-01-07 Impact factor: 7.590