Toll-like receptors activation, signaling, and targeting: an overview

Abstract

Background: Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Such binding is liganddependent and cell type-dependent and leads to production of pro-inflammatory cytokines and type 1 interferon. TLR-dependent signaling pathways are tightly increased during innate immune responses by a variety of negative regulators. Overactivation of TLRs can ultimately lead to disruption of immune homeostasis and thus increase the risk for inflammatory diseases and autoimmune disorders. Antagonists/inhibitors targeting the TLR signaling pathways have emerged as novel therapeutics to treat these diseases. Aim of work: The present review summarizes the structure, characterizations, and signaling of TLRs and their regulators, as well as describes the implication of TLRs in many diseases with a brief idea about the inhibitors that target TLR signaling pathways. Conclusion: We conclude that TLRs are the main elements of our immune system, and they should be maintained functioning to keep the integrity of innate immunity. Targeting of TLR signaling represents a new challenge for treatment of many diseases.

Anti-Inflammatory Activity and ROS Regulation Effect of Sinapaldehyde in LPS-Stimulated RAW 264.7 Macrophages

“…Many studies indicate that the toll-like receptor (TLR) family of pattern recognition receptors include central mediators of the inflammatory response. Accumulating evidence indicates that TLR4 specifically mediates LPS-induced signaling [ 52 ]. The first step in the LPS/TLR4-mediated inflammatory signaling pathway is the binding of LPS to TLR4 complexed with MYD88 adapters at the plasma membrane.…”

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…Although the TLR-pathway is more oriented on the inflammatory response in skeletal muscle [ 151 ], many downstream proteins have broad cellular function, especially MAPK, which plays an important role in cellular proliferation [ 152 ]. From the TLR inhibitors listed as putative stabilizing agents, NI-0101 was used in RA in a Phase II clinical trial and did not show any improvement in the disease parameters [ 153 ].…”

Structure of fish Toll-like receptors (TLR) and NOD-like receptors (NLR)

“…Unlike TLRs, NLRs show a broad category of function that include signal transduction, autophagy, apoptosis regulation, inflammasome assembly and transcription activation. Readers interested to know more about the TLR and NLR domain architecture, signaling molecular pathway and function in human and other higher eukaryotes are referred to published review articles [ 21 , 33 , [38] , [39] , [40] , [41] ]. This review specifically discusses the domain classification (ECD, TIR, CARD and NACHT), structure and function of fish TLR and NLR domains that include TLR2, TLR3, TLR22, NOD1 and NOD2 and downstream molecules like MyD88-TIR, TRIF and RIP2-CARD.…”