Regulation of innate immune responses by transmembrane interactions: Lessons from the TLR family

Abstract

The mammalian innate immune response is responsible for the early stages of defense against invading pathogens. One of the major receptor families facilitating innate immune activation is the Toll-like receptor (TLR) family. These receptors are type 1 membrane proteins spanning the membrane with a single transmembrane domain (TMD). All TLRs form homo- and hetero-dimers within membranes and new data suggest that the single transmembrane domain of some of these receptors is involved in their dimerization and function. Newly identified TLR dimers are continuously reported but only little is known about the importance of the TMDs for their dimer assembly and signaling regulation. Uncontrolled or untimely activation of TLRs is related to a large number of pathologies ranging from cystic fibrosis to sepsis and cancer. In this review we will focus on the contribution of the TMDs of innate immune receptors - specifically TLR2-to their regulation and function. In addition, we will address the current issues remaining to be solved regarding the mechanistic insights of this regulation. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Anti-Inflammatory Effects of Chamaecyparis Obtusa Essential Oil on Peripheral Blood Mononuclear Cells

“…Mastitis is mostly caused by pathogen infection from E. coli, Staphylococcus aureus, and Streptococcus agalactiae [2], and associated endotoxin (LPS) is closely related to inflammation of the mammary gland. LPS initiates cellular inflammatory events and results in activation of NF-κB and production of pro-inflammatory cytokines such as TNF-α and IL-1β [1,24,33].…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…TLRs can form homodimeric and heterodimeric signalling complexes amongst themselves and with RAGE, and also interact with co-receptors (e.g. CD14, MD2); a complexity that contributes to the diversity of cellular responses to different DAMPs [29]. The IL-1R1 receptor is specifically activated by the two IL-1 isoforms, IL-1 and IL-1 .…”

The role of protein–protein interactions in Toll-like receptor function

“…Such ligands cause dimerization by facilitating the formation of stable protein-protein interfaces between TLR chains, either directly, or via coreceptor proteins in the case of TLR4. Dimerization is proposed to initiate a signal, either through homodimerization (TLR 3,4,5,8 & 9) or heterodimerization (TLR 1, 2, 6 & 10) [3,4,[20][21][22][23]. The consequent rearrangements resulting from formation of the dimeric ectodomain complex are transferred via an ill-defined mechanism to the now adjacent carboxy-terminal juxtamembrane and TM helices, inducing dimerization of the cytoplasmic TIR domains.…”

“…The consequent rearrangements resulting from formation of the dimeric ectodomain complex are transferred via an ill-defined mechanism to the now adjacent carboxy-terminal juxtamembrane and TM helices, inducing dimerization of the cytoplasmic TIR domains. These are then proposed to act as a scaffold for the recruitment of adaptor proteins that also contain TIR domains, leading to the formation of higher-order complexes and subsequent transduction of downstream signaling [3,4,10,[20][21][22][23][24].…”

“…Each TLR is composed of an ectodomain responsible for PAMP recognition, a helical transmembrane (TM) domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) domain [3,4,[20][21][22][23]. All TLRs dimerize (TLR1-6) -or reorganize in the case of pre-formed inactive dimeric complexes (TLR7-9) -upon binding of agonistic ligands by the ectodomains.…”