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.
Highlights
The innate immune system, an organism’s first line of defense against invading pathogens, employs a variety of transmembrane and secreted molecules, known as pattern recognition receptors, for the sensing of microbes, the activation of adaptive immunity and complement system, apoptosis, and the induction of proinflammatory mediators
Different pathogenassociated molecular patterns (PAMP) are recognized by different Toll-like receptors (TLR) (Table 1) and include the following: LPS and lipoteichoic acid; peptidoglycan in cell walls, lipoproteins in bacterial capsules, and zymosan; flagellin; unmethylated bacterial or viral CpG DNA; viral RNA; and bacterial RNA (23S rRNA recognized by the orphan receptor TLR13).[6]
The presence of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC) reduces the expression of tumor necrosis factor a (TNF-a), IL-6, and IL-12, while this blockade can be reversed by providing cluster of differentiation 14 (CD14) and LPS-binding proteins in excess to the serum.[113]
Summary
The innate immune system, an organism’s first line of defense against invading pathogens, employs a variety of transmembrane and secreted molecules, known as pattern recognition receptors, for the sensing of microbes, the activation of adaptive immunity and complement system, apoptosis, and the induction of proinflammatory mediators. TLRs were initially described as being involved in the embryonic development of Drosophila.[1] Later, when a homolog of Drosophila Toll, TLR4, was cloned in 1997, it was confirmed that Toll signaling pathways are conserved in humans, where TLRs have important roles in the activation of adaptive immunity.[2] Soon after the discovery of TLR4, it became evident that lipopolysaccharide (LPS), a bacterial cell membrane component, is recognized by TLR4 (pattern recognition receptor), establishing a link between pathogen-associated molecular patterns (PAMPs) and TLRs.[3,4,5] PAMPs are conserved molecular signatures found in different microbes, such as bacteria, viruses, fungi, and protozoa. All TLRs possess a common architecture consisting of three domains: a leucine-rich ectodomain for PAMP recognition; an intracytoplasmic TIR endodomain for adaptor recruitment, such as myeloid differentiation 88 (MyD88), MyD88-adaptor-like (MAL), TIR-domain-containing adaptor-inducing interferon-b (TRIF), and TRIF-related adaptor
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