Table 2.
Exogenous Factors | Ligands | Target Cells | Expression/Activation of TLRs | TLR-Mediated Signal Pathways | Pathophysiological Effect | Ref. |
---|---|---|---|---|---|---|
Cigarette smoke | LPS, DAMPs | AIC, AEC | ↑ TLR2, TLR4 | ↑ MyD88/NF-κB | ↑ IL-8 and other pro-inflammatory cytokines | 19–21,32 |
AEC | ↓ TLR2, TLR4 | – | ↓ Protection of lung tissue from oxidative stress | 20–22 | ||
PMs | LPS, DAMPs | AIC, AEC | ↑ TLR2, TLR4 | ↑ MyD88/NF-κB, ↑ MyD88/AP-1 |
↑ TNF-α, IL-6, IL-8, CCL5, etc. | 17,18,26 |
Bacteria, viruses | LPS | AEC | ↑ TLR4 | ↑ MyD88/NF-κB | ↑ Pro-inflammatory cytokines and chemokines | 31,32 |
NTHi | ↓ TLR2 | ↓ MyD88/NF-κB | ↓ Antimicrobial proteins and peptides | 33 | ||
LPS, Poly I:C, imiquimod/R848 + IL-17, IFN-γ | ↑ TLR3, TLR7 | ↑ MyD88/NF-κB; TRIF-dependent pathway |
↑ IL1-β, IL-6, IL-8, TNF-α, IFN-α, IFN-β, IFN-λ | 8,9,34 | ||
NTHi, MC, SP, LPS, Pam3CSK |
AM | Restimulation of TLR2, TLR4 | ↓MyD88/NF-κB | ↓ TNF-α, CCL5, IL-10, GM-CSF except IL-6 and IL-8; tolerance to bacterial pathogens | 35–37 | |
LPS, Pam3CSK4 | TLR4 stimulation and subsequent TLR2 stimulation | ↑ MyD88/NF-κB | ↑ TNF-α, CCL5, IL-6, IL-8, IL-10 | 36 | ||
Pam3CSK4, zymosan, FSL-1, LPS | L | ↓ TLR2, TLR4 | ↓ MyD88/NF-κB | ↓ GM-CSF, IL-10, IL-1β; tolerance to bacterial pathogens | 39 | |
PM + bacteria | DAMPs + PAMPs | DC, AM | ↓ TLR2, TLR4 | ↓ MyD88/NF-κB | ↓ TNF-α except IL-8; tolerance to bacterial pathogens | 17,25 |
Cigarette smoke + bacteria, viruses | DAMPs + LPS, NTHi, LTA, PGN, lipopeptide amiA, SA, SP | AM, M | ↓ TLR2, TLR4 | ↓ p38, ERK (MAPK), ↓ p65 (NF-kB) |
↓ TNF-α, GM-CSF, IL-6, CCL5 except IL-8 and IL-10; tolerance to bacterial pathogens | 41,42 |
DAMPs + PAMPs | ↑ TLR3 | ↑ TRIF-dependent pathway | ↑ IL-8 | 5 | ||
DAMPs + LTA-containing PGN | M | ↑ TLR2 | ↑ MyD88/NF-κB | ↑ TNF-α, IL-6 | 43 | |
DAMPs + LPS | BN | ↑ TLR2, TLR4, TLR9 | ↑ MyD88/NF-κB | ↑ IL-8, MMP-9; neutrophilic inflammation | 4,10,44 | |
DAMPs + PAMPs | AN | ↓ TLR2 | ↓ MyD88/NF-κB | Tolerance to bacterial pathogens | 45 | |
DAMPs + PAMPs | CTL | ↑ TLR2/1, TLR4, TLR9 | ↑ MyD88/NF-κB | ↑ IL-1β, IL-6, IL-10, IL-12, TNF-α, IFN-γ | 6,7 |
Abbreviations: PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; PMs, particulate matters; LPS, lipopolysaccharide; NTHi, nontypeable Haemophilus influenza; MC, M. catarrhalis; SP, S. pneumoniae; LTA, lipoteichoic acid; SA, S. aureus; SP, S. pneumoniae; PGN, peptidoglycan; MMP-9, matrix metalloproteinase 9; AIC, airway immune cells; AEC, airway epithelial cells; AM, alveolar macrophages; L, leukocytes; DC, dendritic cells; M, monocytes; BN, blood neutrophils; AN, airway neutrophils; CTL, cytotoxic T lymphocytes.