LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation

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.

Peroxisomes in Immune Response and Inflammation

“…The requirement of peroxisomes for the regulation of the macrophages’ response to microbes are conserved from Drosophila to mammals [27]. Further contribution to inflammation by ROS could arise from mitochondria, which are hyperactive and produce elevated levels of superoxide anions in a Drosophila Pex19 mutant [68]. Peroxisome deficiency is also concomitant with an increase in free fatty acids, which are another driver of inflammation [68,69,70].…”

“…Further contribution to inflammation by ROS could arise from mitochondria, which are hyperactive and produce elevated levels of superoxide anions in a Drosophila Pex19 mutant [68]. Peroxisome deficiency is also concomitant with an increase in free fatty acids, which are another driver of inflammation [68,69,70]. While associated with the induction of Hnf4 (Hepatocyte nuclear factor 4), the dysregulated expression of acid lipase expression was identified as a main contributor to mitochondrial damage and swelling due to the high amounts of free fatty acids released from triacylglycerol fat stores, which ultimately triggers the production of high amounts of superoxide anions in mitochondria (Figure 2).…”

The Multi-Omics Architecture of Juvenile Idiopathic Arthritis

“…In a recent in vivo functional study on LACC1 , Skon-Hegg et al demonstrated the important role of LACC1 in inflammatory responses [ 18 ]. As shown in this study, LACC1 knockout mice showed worse disease in the Citrobacter rodentium model of colitis, and the collagen-induced arthritis models, compared to wild type (WT) mice, while there were no differences identified between LACC1 KO and WT in the dextran sulfate sodium (DSS) model of colitis and the K/BxN model of arthritis [ 18 ]. Besides JIA, the pathogenic effects of LACC1 mutation I254V have been correlated with other diseases, e.g., inflammatory bowel disease [ 19 ], leprosy [ 20 ], and Behçet disease [ 21 ].…”

Genome Wide Analysis for Growth at Two Growth Stages in A New Fast-Growing Common Carp Strain (Cyprinus carpio L.)

“…DCs and T cells in semaphorin-4A (Sema4a)-knockout mice displayed poor allostimulatory activities and T helper cell (Th) differentiation, respectively 22 . Spinster homolog 2 (SPNS2) regulates the levels of Sphingosine-1-phosphate (S1P) gradient that controls lymphocyte trafficking 23 . In addition, dnaJ homolog subfamily C member 25 (DNAJC25) can significantly increase cell apoptosis, and its overexpression inhibits cell growth 24 .…”