TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8-or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9 −/− ) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8 −/− or TLR9 −/− mice. On the cellular level, TLR8 −/− and TLR8/ 9 −/− dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9 −/− cells responded normally. Moreover, B cells from TLR9 −/− and TLR8/9 −/− mice were hyperesponsive to R848, but TLR8 −/− B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells. knockout mice | innate immunity | endosomal TLRs

TLR8 Senses Bacterial RNA in Human Monocytes and Plays a Nonredundant Role for Recognition of Streptococcus pyogenes

“…Unresponsiveness to these stimuli has been attributed to the absence of a 5-aa motif in the ectodomain of murine TLR8 that is required for ligand recognition (38). However, TLR8 deficiency is associated with the development of autoimmune diseases in mice, possibly by negatively controlling TLR7 expression (39,40).…”

Toll-like receptors: potential targets for lupus treatment

“…However, the deletion of TLR9 in these lupus-prone models does not lead to disease amelioration as predicted but to disease exacerbation, suggesting a protective [41,42] . In addition, although TLR7 and TLR9 act in parallel on different subsets of autoantibodies, TLR9 suppresses the production of TLR7-dependent, RNAassociated autoantibodies [42,43] . The proportions of TLR9-expressing B cells, plasma cells and monocytes increase in SLE patients, and the increase in TLR9-expressing B cells is correlated with the production of anti-dsDNA antibodies [44,45] .…”

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…All procedures were carried out in accordance with the regulations stipulated by the Animal Use and Protection Committee at Tianjin Medical University and conformed to The Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision research. A truncated form of IRBP peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] was synthesized and purified by Sangon (Shanghai, China). Mycobacterium tuberculosis strain H37RA was obtained from Difco (Detroit, MI).…”

“…Among the TLR family, TLR7 is activated by ssRNAs and is strongly expressed by DCs. TLR7 was implicated in a variety of autoimmune disorders (12)(13)(14), and engagement of TLR7 endows human DCs with the ability to regulate the effector function of Th17 cells (15,16). Recently, targeting cell surface TLR7 in DCs was shown to be a promising strategy for treating autoimmune diseases (17).…”