Review: Toll-like receptors and NOD-like receptors in pulmonary antibacterial immunity

Abstract

Lung diseases caused by bacteria are a leading cause of death in both immunocompromised and immunocompetent individuals as well as in children. Although neutrophil recruitment is critical to augment the host defence, excessive neutrophil accumulation results in life-threatening diseases, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Therefore, it is important to modulate excessive neutrophil influx in ALI/ARDS to mitigate lung damage and mortality. A better understanding of the basic mechanisms underlying neutrophil influx is crucial to designing novel and innovative treatment strategies for ALI/ARDS. Recognition of bacteria in the lung is the critical first step leading to neutrophil influx. Pattern recognition receptors, such as Toll-like receptors and NOD-like receptors, play an important role in the recognition of bacterial pathogens. Understanding the molecular and cellular mechanisms associated with the recognition of bacterial pathogens by the host is critical for the development of effective therapeutic strategies to control parenchymal damage via modulating neutrophil accumulation in the lung.

Fig. 1

Respiratory pathogens are recognised by membrane bound and cytoplasmic pattern recognition receptors. Plasma membrane-bound TLRs (TLR2, TLR4 and TLR5) and endosome membrane-bound TLRs (TLR3, TLR7, TLR8 and TLR9) recognise bacterial pathogens in the lungs. TLR2, TLR4, TLR5, TLR6, TLR7 and TLR9 recruit MyD88 whereas TLR2 and TLR4 recruit both TIRAP and MyD88. TLR3 and TLR4 recruit TRIF to induce downstream signalling cascades. Binding of pathogens and/or PAMPs to TLRs leads to complex signalling cascades, which result in transcription of pro-inflammatory mediators and activation of MAP kinases. Cytosolic NODs recognise bacterial pathogens in the lung and mediate signalling via RIP2, whereas NALPs use ASC to induce signalling cascades, which result in transcription of pro-inflammatory mediators and activation of MAP kinases. These pro-inflammatory mediators, including chemokines, recruit neutrophils to the lung in order to clear the causative organism during bacterial infection.