Toll-Like Receptor Signaling in the Establishment and Function of the Immune System

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.

The role of Toll-like receptors and neuroinflammation in Parkinson’s disease

“…The intracellular section contains an evolutionary-conserved carboxy-terminal domain, denominated Toll/interleukin-1 receptor (TIR) domain, interacting with the TIR or death domain (DD) of adaptor molecules [ 17 ]. These receptors are expressed in a variety of immune and non-immune cells, including macrophages, lymphocytes, dendritic cells (DCs), granulocytes, hematopoietic stem cells (HSCs), epithelial cells, neuronal cells, and endothelial cells [ 18 – 20 ]. They usually function as homodimers, with the exception of TLR2, which forms heterodimers with TLR1, or TLR6, each showing a different ligand specificity [ 21 ].…”

“…They usually function as homodimers, with the exception of TLR2, which forms heterodimers with TLR1, or TLR6, each showing a different ligand specificity [ 21 ]. In humans, four TLRs, including TLR3, TLR7, TLR8, and TLR9, are located within the endosomal membrane, while the other six TLRs reside in the cells' plasma membrane [ 20 ]. Generally, plasma membrane-resided TLRs (TLR 1, 2, 4, 5, 6, and 10) recognize bacterial-related lipid, protein, and lipoprotein compartments, including bacterial flagellin, lipoteichoic acid (LTA), lipopolysaccharide (LPS), di-acylated proteins, and tri-acylated lipoproteins [ 22 ].…”

“…TLR4 can utilize both MyD88 and TRIF pathways [ 31 ]. Through the MyD88-dependent pathway, activated TLR recruits MyD88, followed by three members of the serine-threonine kinase interleukin-1 receptor-associated kinase (IRAK) family, including IRAK1, IRAK2, and IRAK4 [ 32 ], forming a complex called "Myddosome" [ 20 ]. Myddosome then recruits and stimulates the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) by K63-related autoubiquitylation.…”

“…TAK1 then activates mitogen-activated protein kinases 3/6 (MKK3/6), MKK4/7, and the IKKb subunit of IKK. After that, MKK3/6, MKK4/7, and IKK activate P38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinases (JNKs), and P65 NF-kB, respectively, leading ultimately to the transfer of these transcription factors to the nucleus and transcription and synthesis of proinflammatory cytokines such as IL-1, IL-6, and TNF-α [ 15 , 20 ].…”

The Rationale and Current Status of Endotoxin Adsorption in the Treatment of Septic Shock

“…LPS molecules in the bacterial cell wall and also soluble LPS-aggregates are dissociated and bound by LPS Binding Protein (LBP), carried to form a complex with either a soluble or membrane bound cluster of differentiation-14 (CD14), and subsequently transferred to the toll-like receptor 4/myeloid differentiation-2 (MD-2) complex, which promotes the TLR4/MD-2 dimerization necessary for activating intracellular MyD88-dependent and TRIF-dependent pathways. Both pathways lead to the production and release of pro-inflammatory cytokines and type I interferones (IFNs), respectively [26][27][28]. Immune hyperactivation from the inappropriate triggering by pathogens and the cytokine storm leads to organ damage, multi-organ failure, and death [29].…”