Negative regulatory approaches to the attenuation of Toll-like receptor signaling

Toll-like receptors (TLRs) are pivotal components of the innate immune response, which is responsible for eradicating invading microorganisms through the induction of inflammatory molecules. These receptors are also involved in responding to harmful endogenous molecules and have crucial roles in the activation of the innate immune system and shaping the adaptive immune response. However, TLR signaling pathways must be tightly regulated because undue TLR stimulation may disrupt the fine balance between pro- and anti-inflammatory responses. Such disruptions may harm the host through the development of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Several studies have investigated the regulatory pathways of TLRs that are essential for modulating proinflammatory responses. These studies reported several pathways and molecules that act individually or in combination to regulate immune responses. In this review, we have summarized recent advancements in the elucidation of the negative regulation of TLR signaling. Moreover, this review covers the modulation of TLR signaling at multiple levels, including adaptor complex destabilization, phosphorylation and ubiquitin-mediated degradation of signal proteins, manipulation of other receptors, and transcriptional regulation. Lastly, synthetic inhibitors have also been briefly discussed to highlight negative regulatory approaches in the treatment of inflammatory diseases. The immune system is tightly regulated to strike a balance between defense against invading pathogens and inappropriate inflammatory responses. In a review article, Sangdun Choi and his colleagues at Ajou University, Korea, discuss how proteins known as ‘Toll-like receptors’ (TLRs) — the body's first line defense for detecting microbial infections — are kept in check through a number of molecular mechanisms. These include breaking up complexes of TLRs and interacting activators; downregulating the transcription and translation of TLR genes; or degrading TLR proteins directly. The molecules involved in these negative regulatory pathways provide potential therapeutic targets for treating both bacterial disease and autoimmune disorders. To that end, the authors describe a number of synthetic inhibitors that have been tested for their ability to attenuate TLR signaling.