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

Abstract

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.

Figure 1

Overview of the Toll-like receptor (TLR) signaling pathway. When TLRs are stimulated by their respective ligands, they dimerize and recruit downstream adaptor molecules, such as myeloid differentiation primary-response protein 88 (MyD88), MyD88-adaptor-like (MAL), Toll/interleukin (IL)-1 receptor (TIR)-domain-containing adaptor-inducing interferon-β (TRIF), TRIF-related adaptor molecule (TRAM), which activate other downstream molecules leading to the activation of signaling cascades that converge at the nuclear factor-κB (NF-κB), interferon (IFN) response factors (IRFs) and mitogen-activated protein (MAP) kinases. These molecules induce the transcription of several proinflammatory molecules, such as interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor α (TNF-α). The secretion of these molecules counters the threat posed by microbes and helps activate other immune components. AP1, activator protein 1; ATF, activating transcription factor; dsRNA, double-stranded RNA; ERK, extracellular signal-regulated kinase; IKK, inhibitor of kappa light polypeptide gene enhancer in B-cell kinase; IRAK, IL-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MD, myeloid differentiation factor; MKK, MAPK kinase; NA, nucleic acid; TAB, transforming growth factor-β-activated kinase 1/MAP3K7-binding protein; TAK, transforming growth factor-activated kinase; TRAF, tumor necrosis factor receptor-associated factor; RIP1, receptor-interacting protein 1.

Figure 2

Regulatory checkpoints in the Toll-like receptor (TLR) pathway. Subsequent to stimulation with their cognate ligands, TLRs induce several mediators converging at nuclear factor-κB (NF-κB), which mobilizes the transcription of inflammatory genes. This helps the host prepare to fight the microbial threat. After eliminating the threat, the cell must turn off the expression of inflammatory mediators. Sustained activation and overactivation of TLRs are usually accompanied by deleterious consequences for the host. To prevent these consequences, the cell employs a variety of mechanisms to regulate TLR signaling, including decoy factors, adaptor modification, ubiquitin-mediated degradation, promoter state alteration, and translation disruption. All these mechanisms, individually or in combination, exert the effect of controlling inflammation and supporting the system to regain its normal state (arrows in red indicate the irreversible regulation, whereas the others show the reversible regulation).

Figure 3

Model of the Toll-like receptor (TLR)-dependent pro- and anti-inflammatory balance. During homeostasis, when pathogen/damage-associated molecular patterns (PAMPs/DAMPs) breach the protective barrier, TLRs sense these patterns and mount an inflammatory response. As part of the inflammatory response, TLRs activate negative regulators, which have also shown to be triggered by inflammatory cytokines. The inflammatory response neutralizes the danger, and negative regulators prevent the overactivation of the immune system to protect the host. In the case of lack of appropriate TLR stimulation, the propagation of signals, or the induction of an inflammatory mediator, bacteremia may occur, whereas overactivation of any component leads to the development of inflammatory diseases and septic shock.