Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Abstract

Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.arthritis ͉ encephalomyelitis ͉ synthetic agonist

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

“…In the only study examining this concept in EAE, tolerance induction using TLR7 ligands was shown to attenuate active immunization (i.e., not adoptive transfer) EAE models (23). However, in that study, it was also demonstrated that the TLR7 ligands cross-tolerized to TLR2.…”

“…TLR tolerance in autoimmunity, although investigated in a murine model of type 1 diabetes (28), has rarely been studied in the context of either TLR2 or EAE (23,28). In the only study examining this concept in EAE, tolerance induction using TLR7 ligands was shown to attenuate active immunization (i.e., not adoptive transfer) EAE models (23).…”

“…Therefore, we asked whether our 5-d TLR2 tolerance protocol induces crosstolerance to signaling through other TLR molecules. A number of TLRs, including TLR9, TLR7, and TLR4, have been suggested to be important in the pathogenesis of EAE (6,8,(23)(24)(25). Because there has been much evidence that TLR2 and TLR4 usually cross-tolerize each other (22,26), but less documentation that TLR2 can crosstolerize TLR7 and TLR9, we specifically asked whether our TLR2 tolerance induction protocol cross-tolerizes mice to TLR7 and TLR9.…”

Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production

“…Significantly, FcgRIIB-deficient mice develop lupus-like symptoms, indicating the importance of these inhibitory mechanisms in maintaining self-tolerance (36). The role of SHIP-1 in TLR7-dependent tolerance induction and development of autoimmunity has been demonstrated in a murine model of autoimmune encephalitis (42). Critically, both IL-1R-associated kinase IRAK-M and SHIP-1 are upregulated in response to prestimulation of cells with TLR7 agonists and subsequently negatively regulate cytokine production following subsequent treatment of cells with TLR2, TLR7, and TLR9 ligands (42).…”

“…The role of SHIP-1 in TLR7-dependent tolerance induction and development of autoimmunity has been demonstrated in a murine model of autoimmune encephalitis (42). Critically, both IL-1R-associated kinase IRAK-M and SHIP-1 are upregulated in response to prestimulation of cells with TLR7 agonists and subsequently negatively regulate cytokine production following subsequent treatment of cells with TLR2, TLR7, and TLR9 ligands (42). These recent studies highlight the importance of SHIP-1 as a negative regulator of TLR signaling and its potential importance in autoimmunity.…”