TY - JOUR
T1 - Toll-like receptors 2, 4, and 9 modulate promoting effect of COPD-like airway inflammation on K-ras-driven lung cancer through activation of the MyD88/NF-ĸB pathway in the airway epithelium
AU - Velasco, Walter V.
AU - Khosravi, Nasim
AU - Castro-Pando, Susana
AU - Torres-Garza, Nelly
AU - Grimaldo, Maria T.
AU - Krishna, Avantika
AU - Clowers, Michael J.
AU - Umer, Misha
AU - Tariq Amir, Sabah
AU - Del Bosque, Diana
AU - Daliri, Soudabeh
AU - De La Garza, Maria Miguelina
AU - Ramos-Castaneda, Marco
AU - Evans, Scott E.
AU - Moghaddam, Seyed Javad
N1 - Publisher Copyright:
Copyright © 2023 Velasco, Khosravi, Castro-Pando, Torres-Garza, Grimaldo, Krishna, Clowers, Umer, Tariq Amir, Del Bosque, Daliri, De La Garza, Ramos-Castaneda, Evans and Moghaddam.
PY - 2023
Y1 - 2023
N2 - Introduction: Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse. Methods: In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma. Results: We found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding. Discussion: Our study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.
AB - Introduction: Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse. Methods: In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma. Results: We found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding. Discussion: Our study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.
KW - COPD
KW - IKK beta
KW - KRAS
KW - MyD88
KW - lung cancer
KW - toll-like receptor
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U2 - 10.3389/fimmu.2023.1118721
DO - 10.3389/fimmu.2023.1118721
M3 - Article
C2 - 37283745
AN - SCOPUS:85161058157
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1118721
ER -