Intrinsic and extrinsic regulation of innate immune receptors

Abstract

Pattern recognition receptors (PRRs) in innate immune cells play a pivotal role in the first line of host defense system. PRRs recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to initiate and regulate innate and adaptive immune responses. PRRs include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), which have their own features in ligand recognition and cellular location. Activated PRRs deliver signals to adaptor molecules (MyD88, TRIF, MAL/TIRAP, TRAM, IPS-1) which act as important messengers to activate downstream kinases (IKK complex, MAPKs, TBK1, RIP-1) and transcription factors (NF-κB, AP-1, IRF3), which produce effecter molecules including cytokines, chemokines, inflammatory enzymes, and type I interferones. Since excessive PRR activation is closely linked to the development of chronic inflammatory diseases, the role of intrinsic and extrinsic regulators in the prevention of over- or unnecessary activation of PRRs has been widely studied. Intracellular regulators include MyD88s, SOCS1, TOLLIP, A20, and CYLD. Extrinsic regulators have also been identified with their molecular targets in PRR signaling pathways. TLR dimerization has been suggested as an inhibitory target for small molecules such as curcumin, cinnamaldehyde, and sulforaphane. TBK1 kinase can be a target for certain flavonoids such as EGCG, luteolin, quercetin, chrysin, and eriodictyol to regulate TRIF-dependent TLR pathways. This review focuses on the features of PRR signaling pathways and the therapeutic targets of intrinsic and extrinsic regulators in order to provide beneficial strategies for controlling the activity of PRRs and the related inflammatory diseases and immune disorders.

Fig. 1

Intracellular signaling pathways of pattern-recognition receptors. TLRs are mostly present on the membrane. RLRs and NLRs are located in the cytosol. TLRs send signal through Mal/TIRAP and MyD88 or TRAM/TRIF to IRAK/TRAF6 to activate downstream kinases. RLRs use IPS-1 and TRAF3 as adaptor molecules and NLRs transmit activation signals through TRAF6. The signals from TLRs, RLRs, and NLRs are delivered to kinases such as MAPKs, IKKs, TBK1, RIP-1, and RICK to activate transcription factor, AP-1, NF-κB, and IRF. Transcription factors bind to specific DNA sequences and produce effecter molecules such as cytokines, inflammatory enzymes, chemokines, and type I interferons (IFNs).

Fig. 2

Endogenous and exogenous regulators of TLR activation. Endogenous negative regulators of TLRs are revealed. The short form of MyD88 (sMyD88) substitutes MyD88 but cannot send signals downstream. Tollip interacts with IRAK to decrease phosphorylation. A20 deubiquitylates TRAF6. SOCS1 regulates phosphoryltation of IκBα, p38, and JNK. Exogenous TLR regulators have been identified. Small molecules such as surforaphane, cinnamaldehyde, and curcumin block oligomerization of the receptor, whereas resveratrol, EGCG, and certain flavonoids such as lutelolin, quercetin, chrysin, and eriodictyol have the ability to decrease kinase activity of TBK1. In addition, ligand binding to the receptor complex can be another target for regulation of the TLR signaling pathway.