Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation

• Published in: Scientific reports 2016-04, Vol.6 (1), p.24477-24477, Article 24477
• Main Authors: Takagi, Hideaki, Arimura, Keiichi, Uto, Tomofumi, Fukaya, Tomohiro, Nakamura, Takeshi, Choijookhuu, Narantsog, Hishikawa, Yoshitaka, Sato, Katsuaki
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/21; 13/31; 13/51; 13/95; 631/250/24; 631/250/249/1313/1758; 64/110; Adaptive Immunity; Animals; Autoimmune diseases; Autoimmune Diseases - physiopathology; Autoimmunity; Dendritic cells; Dendritic Cells - immunology; Dermatitis; Dermatitis - physiopathology; Disease Models, Animal; Glomerulonephritis - physiopathology; Humanities and Social Sciences; Immune response; Immunity, Innate; Immunology; Inflammation; Inflammation - physiopathology; Innate immunity; Interferon; Lupus; Lymphocytes T; Mice; multidisciplinary; Nucleic acids; Psoriasis; Psoriasis - physiopathology; Science; Skin - pathology; Skin diseases; Systemic lupus erythematosus; T cell receptors; Toll-Like Receptor 7 - metabolism; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24477

Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Plasmacytoid dendritic cells (pDCs) are cells specialized in robust IFN-I secretion by the engagement of endosomal TLRs and predominantly express sialic acid-binding Ig-like lectin (Siglec)-H. However, how pDCs control endosomal TLR-mediated immune responses that cause autoimmunity remains unclear. Here we show a critical role of pDCs in TLR7-mediated autoimmunity using gene-modified mice with impaired expression of Siglec-H and selective ablation of pDCs. pDCs were shown to be indispensable for the induction of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. pDCs aggravated psoriasiform dermatitis mediated through the hyperproliferation of keratinocytes and enhanced dermal infiltration of granulocytes and γδ T cells. Furthermore, pDCs promoted the production of anti-self NA antibodies and glomerulonephritis in lupus-like disease by activating inflammatory monocytes. On the other hand, Siglec-H regulated the TLR7-mediated activation of pDCs. Thus, our findings reveal that pDCs provide an essential link between TLR7-mediated innate and adaptive immunity for the initiation of IFN-I-associated autoimmune inflammation.