TY - JOUR
T1 - PEP-sNASP Peptide Alleviates LPS-Induced Acute Lung Injury Through the TLR4/TRAF6 Axis
AU - Wu, Yu-Chih
AU - Hsu, Sung-Po
AU - Hu, Meng-Chun
AU - Lan, Yu-Ting
AU - Yeh, Edward T H
AU - Yang, Feng-Ming
N1 - Funding Information:
This work was financially supported of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. F-MY was also supported by grants (TMU 108-AE1-B14, DP2-109-21121-01-T-04-02, and DP2-110-21121-01-T-04-02) from Taipei Medical University and (MOST 108-2320-B-038-069-MY2 and MOST 110-2320-B-038-065-MY3) from the Ministry of Science and Technology of Taiwan. Y-CW was also supported by grants (TMU 105-AE1-B53) from Taipei Medical University.
Publisher Copyright:
Copyright © 2022 Wu, Hsu, Hu, Lan, Yeh and Yang.
PY - 2022/3/21
Y1 - 2022/3/21
N2 - Acute lung injury (ALI) is a severe inflammatory lung disease associated with macrophages. Somatic nuclear autoantigenic sperm protein (sNASP) is a negative regulator of Toll-like receptor (TLR) signaling that targets tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in macrophages, which is required to maintain homeostasis of the innate immune response. In the present study, we generated a cell permeable PEP-sNASP peptide using the sNASP protein N-terminal domain, and examined its potential therapeutic effect in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, PEP-sNASP peptide treatment markedly ameliorated pathological injury, reduced the wet/dry (W/D) weight ratio of the lungs and the production of proinflammatory cytokines (interleukin (IL)-1β, IL-6, and TNF-α). In vitro, we demonstrated that when the PEP-sNASP peptide was transduced into RAW 264.7 cells, it bound to TRAF6, which markedly decreased LPS-induced proinflammatory cytokines by inhibiting TRAF6 autoubiquitination, nuclear factor (NF)-κB activation, reactive oxygen species (ROS) and cellular nitric oxide (NO) levels. Furthermore, the PEP-sNASP peptide also inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Our results therefore suggest that the PEP-sNASP may provide a potential protein therapy against oxidative stress and pulmonary inflammation via selective TRAF6 signaling.
AB - Acute lung injury (ALI) is a severe inflammatory lung disease associated with macrophages. Somatic nuclear autoantigenic sperm protein (sNASP) is a negative regulator of Toll-like receptor (TLR) signaling that targets tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in macrophages, which is required to maintain homeostasis of the innate immune response. In the present study, we generated a cell permeable PEP-sNASP peptide using the sNASP protein N-terminal domain, and examined its potential therapeutic effect in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, PEP-sNASP peptide treatment markedly ameliorated pathological injury, reduced the wet/dry (W/D) weight ratio of the lungs and the production of proinflammatory cytokines (interleukin (IL)-1β, IL-6, and TNF-α). In vitro, we demonstrated that when the PEP-sNASP peptide was transduced into RAW 264.7 cells, it bound to TRAF6, which markedly decreased LPS-induced proinflammatory cytokines by inhibiting TRAF6 autoubiquitination, nuclear factor (NF)-κB activation, reactive oxygen species (ROS) and cellular nitric oxide (NO) levels. Furthermore, the PEP-sNASP peptide also inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Our results therefore suggest that the PEP-sNASP may provide a potential protein therapy against oxidative stress and pulmonary inflammation via selective TRAF6 signaling.
KW - NASP
KW - TLR4
KW - TRAF6
KW - acute lung injury
KW - inflammation
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U2 - 10.3389/fmed.2022.832713
DO - 10.3389/fmed.2022.832713
M3 - Article
C2 - 35386914
SN - 2296-858X
VL - 9
SP - 832713
JO - Frontiers in Medicine
JF - Frontiers in Medicine
M1 - 832713
ER -