TLRs in pulmonary diseases

Abstract

Toll-like receptors (TLRs) comprise a clan of proteins involved in identification and triggering a suitable response against pathogenic attacks. As lung is steadily exposed to multiple infectious agents, antigens and host-derived danger signals, the inhabiting stromal and myeloid cells of the lung express an aggregate of TLRs which perceive the endogenously derived damage-associated molecular patterns (DAMPs) along with pathogen associated molecular patterns (PAMPs) and trigger the TLR-associated signalling events involved in host defence. Thus, they form an imperative component of host defence activation in case of microbial infections as well as non-infectious pulmonary disorders such as interstitial lung disease, acute lung injury and airways disease, such as COPD and asthma. They also play an equally important role in lung cancer. Targeting the TLR signalling network would pave ways to the design of more reliable and effective vaccines against infectious agents and control deadly infections, desensitize allergens and reduce inflammation. Moreover, TLR agonists may act as adjuvants by increasing the efficiency of cancer vaccines, thereby contributing their role in treatment of lung cancer too. Overall, TLRs present a compelling and expeditiously bolstered area of research and addressing their signalling events would be of significant use in pulmonary diseases.

Keywords: Asthma; COPD; DAMPs; Lung interstitial diseases; PAMPs; Toll-like receptors (TLRs).

Graphical abstract

Fig. 1

TLR signalling - TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are expressed on the surface of the cell whereas TLR3, TLR7, TLR8 and TLR9 in intracellular vesicles like endosome and lysosomes. All TLRs except TLR3 activates MyD88 pathway, TLR3 and TLR4 activate TRIF pathway. When ligand binds to the TLR receptors, adaptor molecules MyD88 and TRIF bind to the TIR domain either directly or indirectly via bridge molecules TIRAP and TRAM. MyD88 now recruits IRAK4 which in turn phosphorylate and activate IRAK1/2. The activated IRAKs now interact with TRAF6. This IRAK-TRAF6 complex recruits and activates TAK1. It also gets activated directly by MyD88 and RIP1. Activated TAK1 activates IKK complex and MAPKs. IKK complex phosphorylates and subsequently degrade Iκβ by proteasomes leading to release of transcription factor (TF) NF-κβ whereas activated MAPKs releases transcription factor AP1 by activating JNK1/2 and p38. These TFs translocate into the nucleus and bind to their corresponding TF binding segment on the DNA to induce transcription of cytokines, chemokines, interferons, interleukins etc. In TRIF pathway, TRIF binds to TIR domain via bridge molecule TRAM. TRIF binds TRAF3 and TRAF6. By binding to TRAF6 it normally activates MyD88 pathway whereas by binding with TRAF3 it activates TKB1 which further phosphorylates and activates IRF3 and IRF7. Their homodimers enter nucleus and binds to its binding segment on DNA and transcribe IFN-α and IFN-β.