Table 2.

The Mechanisms of the Influence of Exogenous Factors on TLR Signal Pathways in COPD

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.