TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

Abstract

Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE) 1,2 . However, regimens used to treat many such conditions cannot maintain disease control in the majority of SLE patients and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reductions in disease activity 3,4 . The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-κB inhibition 5 . Recognition of self nucleic acids by toll-like receptors TLR7 and TLR9 on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE 6 , promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease 1,7 . Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues 8,9 . We demonstrate, in vitro and in vivo, that stimulation of PDCs through TLR7 and 9 can account for the reduced activity of glucocorticoids to inhibit the IFN pathway in SLE patients and in two lupus-prone mouse strains. The triggering of PDCs through TLR7 and 9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-κB pathway essential for PDC survival. Glucocorticoids do not affect NF-κB activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-α levels. These findings unveil a new role for self nucleic acid

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

“…The finding that basal splenic IDO expression levels were elevated in unmanipulated MRL lpr/lpr mice suggests that increased IDO is a physiologic response to increased inflammation in presymptomatic in lupus-prone mice (24)(25)(26)32). Functionally, we show that IDO was mechanistically important in controlling disease progression, because inhibition of IDO caused a rapid acceleration of disease.…”

“…Increased IDO in these situations acts to attenuate harmful inflammation, as shown by the marked exacerbation of disease in all of these models when IDO is inhibited. Lupus-prone Murphy Roths large (MRL) lpr/lpr mice show a prolonged period of chronic inflammation and autoimmunity before the development of overt disease (23)(24)(25)(26). We asked whether IDO function was involved in limiting development of systemic autoimmune disease in MRL lpr/lpr mice.…”

Up-regulated Complement 3 Production by Toll-like receptor 9/ Transforming Growth Factor-Beta 1/Complement 3 Pathway in Whole Blood Cells of Lupus Thrombocytopenia

“…These findings support the notion that glucocorticoid can inhibit endogenous DNA-activated TLR9 and nuclear factor-kappa B activation in SLE patients with TCP. 26 Thus, blocking TLR9 could down-regulate C3 gene expression in whole blood cells, which may lead to reduced complement mediated destruction of thrombocytes.…”

The Role of B-Cells and B-Cell Targeted Therapies in Lupus Nephritis

“…This is especially important in light of recent findings that glucocorticoids in murine lupus models fail to inhibit TLR signaling in plasmacytoid dendritic cells. 123 This may partially explain why certain patients do not respond sufficiently to steroid therapy. Several synthetic inhibitory oligonucleotides (INH-ODN) have been generated with the goal of blocking the activation of TLR-9 and TLR-7.…”