TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Abstract

The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

Enhanced TLR2 responses in multiple sclerosis

“…In sum, in this study we document for the first time that a large percentage of MS patients, including patients with progressive forms of the disease, have enhanced responses to TLR2 stimulation. The motivation for our study stemmed from our postulate that patients with MS have defective regulation of TLR2 responses due to a deficiency in chronic exposure to microbiome‐derived TLR2 ligands . Linking the present results with the microbiome will depend upon future studies that correlate low levels of serum microbiome‐derived TLR2 ligands (e.g.…”

“…In this study our goal was to investigate the TLR2 responses of patients with MS using a variety of approaches. Our motivation for characterizing TLR2 responses in MS stemmed from our postulate that patients with MS have a deficiency in innate immune regulation leading to hyper‐responsiveness to TLR2 stimulation . There have been a number of studies attempting to identify the role of TLR2 signalling in the pathogenesis of EAE and MS .…”

“…Although still controversial, most of these suggest that TLR2 signalling plays an important role in mediating the disease process. Additionally, studies from our laboratory and others have suggested the potential for targeting TLR2 as a therapeutic approach in MS . However, there is a lack of consistency in the literature concerning the level of response of MS patients to Toll‐like receptor stimulation and there has been little characterization of the TLR2 responses in MS patients.…”

“…This is predicted to result in enhanced responses to TLR2 ligation, which then play a role in the pathogenesis of the disease. As a proof‐of‐concept we reported recently that decreasing systemic TLR2 responsiveness by administering very low doses of TLR2 ligands significantly attenuated the mouse model of MS, experimental autoimmune encephalomyelitis (EAE) .…”

TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia

“…TLR2 is also associated with the invasive growth pattern of glioma and protumor phenotype reprogramming of DCs (44,45). In the experimental autoimmune encephalomyelitis (EAE) model and in multiple sclerosis patients, TLR2 agonists function as inhibitors of neuroinflammation, and TLR tolerance induces the immune regulatory response to create an immunosuppressive microenvironment (46,47). Our study uncovered the role of TLR2 and its endogenous ligands in downregulating microglial MHC class II expression and elucidated the mechanisms that underlie glioma escape from the attack of infiltrated immune cells.…”