Role of toll-like receptors and nod-like receptors in acute lung infection

Abstract

The respiratory system exposed to microorganisms continuously, and the pathogenicity of these microbes not only contingent on their virulence factors, but also the host's immunity. A multifaceted innate immune mechanism exists in the respiratory tract to cope with microbial infections and to decrease tissue damage. The key cell types of the innate immune response are macrophages, neutrophils, dendritic cells, epithelial cells, and endothelial cells. Both the myeloid and structural cells of the respiratory system sense invading microorganisms through binding or activation of pathogen-associated molecular patterns (PAMPs) to pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs). The recognition of microbes and subsequent activation of PRRs triggers a signaling cascade that leads to the activation of transcription factors, induction of cytokines/5chemokines, upregulation of cell adhesion molecules, recruitment of immune cells, and subsequent microbe clearance. Since numerous microbes resist antimicrobial agents and escape innate immune defenses, in the future, a comprehensive strategy consisting of newer vaccines and novel antimicrobials will be required to control microbial infections. This review summarizes key findings in the area of innate immune defense in response to acute microbial infections in the lung. Understanding the innate immune mechanisms is critical to design host-targeted immunotherapies to mitigate excessive inflammation while controlling microbial burden in tissues following lung infection.

Keywords: NOD (nucleotide binding and oligomerization domain) and leucine rich repeat containing receptor (NLR); Neutrophil; TLR - toll-like receptor; cytokine; lung.

Figure 1

Microbes are recognized 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) recognize bacterial, viral, and fungal lung pathogens and/or PAMPs. TLR4, TLR5, TLR6, TLR7 and TLR9 recruit MyD88 directly to the TIR domain while TLR2 and TLR4 requires TIRAP for the recruitment of MyD88 to the TIR domain. TLR3 recruits TRIF to the TIR domain. Through the MyD88-independent pathway, TLR4 requires TRAM for the recruitment of TRIF. The binding of pathogens and/or PAMPs to TLRs leads to complex downstream signaling cascades that result in transcription of pro-inflammatory mediators and activation of MAP kinases. Cytosolic NOD1 and NOD2 recognize bacterial, viral, and fungal pathogens in the lung and mediate signaling by RIP2. The NLRP3, NLRP6, NLRP12 senses PAMPs using the LRR domain and uses ASC to recruit caspase-1 and induce the downstream signaling cascade, which result in transcription of pro-inflammatory mediators and activation of MAP kinases. The HIN200 domain of AIM2 binds cytoplasmic DNA and recruits ASC and caspase-1 to induce the downstream signaling cascade. NLRC4 does not require ASC to recruit caspase-1. These pro-inflammatory mediators, including chemokines, lead to the regulation of immune cell infiltration to the lung and the induction of inflammation. Created with Biorender.com.