LACC1 regulates TNF and IL-17 in mouse models of arthritis and inflammation

Cara Skon-Hegg, Juan Zhang, Xiumin Wu, Meredith Sagolla, Naruhisa Ota, Arthur Wuster, Jennifer Tom, Emma Doran, Nandhini Ramamoorthi, Patrick Caplazi, John Monroe, Wyne P. Lee, Timothy W. Behrens

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Both common and rare genetic variants of laccase domain-containing 1 (LACC1, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of Citrobacter rodentium, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and C. rodentium colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A-producing CD4+ T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying LACC1 variants.

Original languageEnglish (US)
Pages (from-to)183-193
Number of pages11
JournalJournal of Immunology
Volume202
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Funding Information:
This work was supported by Genentech, Inc.

Publisher Copyright:
© 2018 by The American Association of Immunologists, Inc.

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