Sensors of the innate immune system: their link to rheumatic diseases

Theofilopoulos, Argyrios N.; Gonzalez-Quintial, Rosana; Lawson, Brian R.; Koh, Yi Ting; Stern, Michael E.; Kono, Dwight H.; Beutler, Bruce; Baccalà, Roberto

doi:10.1038/nrrheum.2009.278

Cited by 81 publications

(65 citation statements)

References 105 publications

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“…Interestingly, these endosomal TLRs are also able to detect self-nucleic acids (12)(13)(14). Although the endosomal localization isolate TLR3, TLR7, TLR8, and TLR9 away from self-nucleic acids in the extracellular space, still self-RNA or -DNA can become a potent trigger of cell activation when transported into TLR-containing endosomes, and such recognition can result in sterile inflammation and autoimmunity, including SLE (4,15,16). The connection of the endosomal TLRs with SLE originates mainly from mouse models, where TLR7 signaling seems to play a central role.…”

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confidence: 99%

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

Desnues

Macedo

Roussel‐Queval

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

105

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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

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confidence: 99%

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

Desnues

Macedo

Roussel‐Queval

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

105

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“…Recently, lots of attention was drawn to studies demonstrating inflammasome activation and IL-1b release in macrophages exposed to MSU or CPPD crystals (6,(15)(16)(17). These findings identified IL-1b as a central mediator and a novel therapeutic target of inflammation in crystal-induced joint diseases (18,19). Anti-IL-1b Ab-based therapies have been successfully used to dampen joint inflammation in gout patients (20).…”

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confidence: 99%

Pseudogout-Associated Inflammatory Calcium Pyrophosphate Dihydrate Microcrystals Induce Formation of Neutrophil Extracellular Traps

Pang

Hayes

Buac

et al. 2013

The Journal of Immunology

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Pseudogout is an autoinflammatory condition triggered by calcium pyrophosphate dehydrate (CPPD) crystal deposition in the joints. The innate immune system is irritated by and responds to the presence of the crystals with an inflammatory response. The synovial fluid contains activated inflammatory macrophages and neutrophil granulocytes. Several details of crystal-induced macrophage activation were recently uncovered, but very little is known about interactions of CPPD crystals with neutrophils. In this study, we show that human neutrophils engulf CPPD crystals and form large amounts of neutrophil extracellular traps (NETs) in vitro. Released extracellular DNA binds myeloperoxidase and citrullinated histone H4. CPPD crystal–stimulated neutrophils and their nuclear DNA undergo morphological changes characteristic for NET formation. The ERK/MEK signaling pathway, heat shock protein 90, PI3K, and an intact cytoskeleton are required for CPPD-induced NET formation. Blocking crystal-activated respiratory burst has, however, no effect on NETs. Human neutrophils release IL-1β and IL-8 in response to CPPD crystals, and blocking CXCR2, the main IL-8R, diminishes NET formation. Proinflammatory cytokines, TNF-α, GM-CSF, and IL-1β, increase NET release by the crystals. Enhanced bacterial killing by CPPD-induced NETs demonstrates their ability to cause cellular damage. Our work documents and provides details about extracellular trap release in human neutrophils activated by CPPD microcrystals. We suggest that crystal-triggered NET formation can be a novel contributor to inflammatory conditions observed in CPPD crystal–driven synovitis.

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“…Similarly, other studies showed that mice carrying double deletion of Tlr7 and Tlr9 had stronger disease reduction than those carrying the single Tlr7 deletion. These results suggested that both TLR7 and TLR9 exert disease-promoting effects and that TLR7 engagement is more pathogenic than TLR9 engagement (24). The differential effects of these TLRs may be attributed to increased availability of TLR7-engaging, RNA-containing particles and/or increased downstream signaling by TLR7 compared with TLR9.…”

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confidence: 95%