Lacc1, also known as C13orf31, is an enzyme highly expressed in inflammatory macrophages. It serves a central regulatory role in multiple inflammatory diseases such as inflammatory bowel diseases, arthritis, and microbial infections [1,2,3,4,5,6,7,8]. Biochemically, Lacc1 converts L-citrulline to L-ornithine (L-Orn) and isocyanic acid, bridging proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism [1,2].

In Lacc1 knockout (KO) mouse models, several key findings have emerged. Lacc1 -/- mice had more severe colon lesions following oral administration of Citrobacter rodentium, and an accelerated onset and worse arthritis in collagen-induced and mannan-induced arthritis models. Serum and local TNF were increased, and the percentage of IL-17A-producing CD4+ T cells was elevated [6]. In the context of intestinal inflammation and bacterial clearance, Lacc1 -/- mice developed more severe T-cell transfer colitis, had an increased bacterial burden in intestinal lymphoid organs, and altered T-cell cytokine profiles [7]. Also, Lacc1 deficiency in mice aggravated dextran sodium sulfate (DSS)-induced inflammatory bowel disease, with significant changes in the intestinal flora [8]. In humans, LACC1 deficiency in macrophages is linked to juvenile idiopathic arthritis, associated with autophagy and metabolism defects [3,5,9].

In conclusion, Lacc1 plays a crucial role in macrophage immunometabolism, inflammation regulation, and bacterial clearance. The study of Lacc1 KO mouse models has significantly enhanced our understanding of its functions in inflammatory diseases like arthritis and inflammatory bowel disease, providing insights into potential therapeutic targets for these conditions.

References:

1. Wei, Zheng, Oh, Joonseok, Flavell, Richard A, Crawford, Jason M. 2022. LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. In Nature, 609, 348-353. doi:10.1038/s41586-022-05111-3. https://pubmed.ncbi.nlm.nih.gov/35978195/

2. Li, Yaling, Wu, Zhixiong, Tan, Xiaoli, Tang, Liang, Ouyang, Fan. 2023. LACC1: A critical involvement in macrophage immunometabolism. In Cell biology international, 47, 1488-1490. doi:10.1002/cbin.12063. https://pubmed.ncbi.nlm.nih.gov/37366569/

3. Omarjee, Ommar, Mathieu, Anne-Laure, Quiniou, Gaëlle, Walzer, Thierry, Belot, Alexandre. . LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages. In The Journal of experimental medicine, 218, . doi:10.1084/jem.20201006. https://pubmed.ncbi.nlm.nih.gov/33606008/

4. Xiong, Yulong, Zhang, Zhenhao, Liu, Shangyu, Zhou, Likun, Yao, Yan. 2023. Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 123, 155193. doi:10.1016/j.phymed.2023.155193. https://pubmed.ncbi.nlm.nih.gov/37976692/

5. He, Tingyan, Wang, Linlin, Huang, Xiaomei, Weng, Ruohang, Yang, Jun. 2024. LACC1 deficiency leading to juvenile arthritis and anemia. In Clinical immunology (Orlando, Fla.), 265, 110290. doi:10.1016/j.clim.2024.110290. https://pubmed.ncbi.nlm.nih.gov/38944365/

6. Skon-Hegg, Cara, Zhang, Juan, Wu, Xiumin, Lee, Wyne P, Behrens, Timothy W. 2018. LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation. In Journal of immunology (Baltimore, Md. : 1950), 202, 183-193. doi:10.4049/jimmunol.1800636. https://pubmed.ncbi.nlm.nih.gov/30510070/

7. Kang, Jung-Woo, Yan, Jie, Ranjan, Kishu, Turner, Jerrold R, Abraham, Clara. 2020. Myeloid Cell Expression of LACC1 Is Required for Bacterial Clearance and Control of Intestinal Inflammation. In Gastroenterology, 159, 1051-1067. doi:10.1053/j.gastro.2020.07.024. https://pubmed.ncbi.nlm.nih.gov/32693188/

8. Xu, Zheng-Yuan, Wang, Jin-Chun. 2023. LACC1 regulates changes in the intestinal flora in a mouse model of inflammatory bowel disease. In BMC gastroenterology, 23, 358. doi:10.1186/s12876-023-02971-5. https://pubmed.ncbi.nlm.nih.gov/37848840/

9. Clarke, Joanna. . LACC1-associated JIA linked to autophagy defects in macrophages. In Nature reviews. Rheumatology, 17, 251. doi:10.1038/s41584-021-00607-0. https://pubmed.ncbi.nlm.nih.gov/33762710/