Slc15a4, an endolysosome-resident transporter, is crucial for Toll-like receptor (TLR) 7-9 as well as nucleotide-binding oligomerization domain-containing protein (NOD) signaling in immune cells [2]. It is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans [2]. It also plays a role in controlling endolysosomal TLR responses and acts as a signaling scaffold [3].

In murine models, loss-of-function mutations or genomic deletions of Slc15a4 abolish responses of nucleic acid-sensing endosomal TLRs and significantly reduce disease in lupus models. For example, homozygous and even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication show disease reduction [4]. Additionally, Slc15a4-deficient mice exhibit amelioration of symptoms of model diseases related to systemic lupus erythematosus and colitis [5]. In human immune cells, deletion of Slc15a4 specifically impairs the activation of the IRF pathway without affecting NF-κB and MAPK signalling, indicating normal ligand recognition and TLR engagement in the endolysosome [1].

In conclusion, Slc15a4 is essential for endolysosomal TLR-mediated inflammatory responses and is crucial in the pathogenesis of autoimmune diseases like systemic lupus erythematosus. The study of Slc15a4 using gene knockout (KO) and conditional knockout (CKO) mouse models has provided valuable insights into its role in these disease processes, highlighting its potential as a therapeutic target for autoimmune and autoinflammatory conditions [2,3,4,5].

References:

1. Heinz, Leonhard X, Lee, JangEun, Kapoor, Utkarsh, Rebsamen, Manuele, Superti-Furga, Giulio. 2020. TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. In Nature, 581, 316-322. doi:10.1038/s41586-020-2282-0. https://pubmed.ncbi.nlm.nih.gov/32433612/

2. Chiu, Tzu-Yuan, Lazar, Daniel C, Wang, Wesley W, Teijaro, John R, Parker, Christopher G. 2024. Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity. In Nature chemical biology, 20, 1000-1011. doi:10.1038/s41589-023-01527-8. https://pubmed.ncbi.nlm.nih.gov/38191941/

3. Zhang, Haobo, Bernaleau, Léa, Delacrétaz, Maeva, Eibel, Hermann, Rebsamen, Manuele. 2023. SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL. In Cell reports, 42, 112916. doi:10.1016/j.celrep.2023.112916. https://pubmed.ncbi.nlm.nih.gov/37527038/

4. Rimann, Ivo, Gonzalez-Quintial, Rosana, Baccala, Roberto, Kono, Dwight H, Theofilopoulos, Argyrios N. 2022. The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2200544119. doi:10.1073/pnas.2200544119. https://pubmed.ncbi.nlm.nih.gov/35349343/

5. Kobayashi, Toshihiko, Nguyen-Tien, Dat, Ohshima, Daisuke, Yoshida-Sugitani, Reiko, Toyama-Sorimachi, Noriko. . Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity. In International immunology, 33, 399-406. doi:10.1093/intimm/dxab006. https://pubmed.ncbi.nlm.nih.gov/33560415/