Interferon‐β regulates the production of IL‐10 by toll‐like receptor‐activated microglia

Lobo‐Silva, Diogo; Carriche, Guilhermina M.; Castro, A. Gil; Roque, Susana; Saraiva, Margarida

Pattern recognition receptors, such as toll‐like receptors (TLRs), perceive tissue alterations and initiate local innate immune responses. Microglia, the resident macrophages of the brain, encode TLRs which primary role is to protect the tissue integrity. However, deregulated activation of TLRs in microglia may lead to chronic neurodegeneration. This double role of microglial responses is often reported in immune‐driven neurologic diseases, as in multiple sclerosis (MS). Consequently, strategies to manipulate microglia inflammatory responses may help to ameliorate disease progression. In this context, the anti‐inflammatory cytokine interleukin (IL)‐10 appears as an attractive target. In this study, we investigated how activation of microglia by TLRs with distinct roles in MS impacts on IL‐10 production. We found that activation of TLR2, TLR4, and TLR9 induced the production of IL‐10 to a greater extent than activation of TLR3. This was surprising as both TLR3 and IL‐10 play protective roles in animal models of MS. Interestingly, combination of TLR3 triggering with the other TLRs, enhanced IL‐10 through the modulation of its transcription, via interferon (IFN)‐β, but independently of IL‐27. Thus, in addition to the modulation of inflammatory responses of the periphery described for the axis TLR3/IFN‐β, we now report a direct modulation of microglial responses. We further show that the presence of IFN‐γ in the microenvironment abrogated the modulation of IL‐10 by TLR3, whereas that of IL‐17 had no effect. Considering the therapeutic application of IFN‐β in MS, our study bears important implications for the understanding of the cytokine network regulating microglia responses in this setting.