Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS.
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Data availability statement
The data underlying this article is available in NCBI-GEO at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66890, and can be accessed with GSE66890.
Abbreviations
- ALI:
-
Acute lung injury
- ARDS:
-
Acute respiratory distress syndrome
- SARS:
-
Severe acute respiratory syndrome
- miRNA:
-
microRNA
- RISC:
-
RNA-induced silencing complex
- DEGs:
-
Differentially expressed genes
- WGCNA:
-
Weighted gene co-expression network analysis
- FFL:
-
Feed-forward loop
- TFs:
-
Transcription factors
- MD:
-
Molecular dynamics
- CLP:
-
Cecal ligation puncture
- NCBI:
-
National Center for Biotechnology Information
- GEO:
-
Gene expression omnibus
- HGNC:
-
HUGO Gene Nomenclature Committee
- ME:
-
Module Eigengene
- MM:
-
Module membership
- GS:
-
Gene significance
- MM/PBSA:
-
Molecular mechanics/Poisson‐Boltzmann surface area
- RMSD:
-
Root mean square deviation
- RMSF:
-
Root mean square fluctuation
- \({{R}}_{{g}}\) :
-
Radius of gyration
- TLR6:
-
Toll-like receptor 6
- STAT6:
-
Signal transducer and activator of transcription 6
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Acknowledgements
Prithvi Singh would like to thank the Indian Council of Medical Research (ICMR) for awarding him Senior Research Fellowship [Grant Number: BMI/11(89)/2020]. Indrakant Kumar Singh would like to thank ICMR [Grant Number: ISRM/12(58)/2020] and Department of Health Research (DHR), Government of India (Grant Number: LTFTII-ID-2021-2013) for providing him financial assistance. Prakash Jha would like to thank the Department of Science & Technology (DST), Government of India for awarding him DST-INSPIRE fellowship (Grant Number: DST/INSPIRE/03/2016/000026). Madhu Chopra would like to thank the Department of Biotechnology (DBT), Government of India (grant number: BT/PR40153/BTIS/137/8/2021) for providing Bioinformatics Infrastructure Facility (BIF) at Dr. B. R. Ambedkar Center for Biomedical Research (ACBR).
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MJK: conceptualization, methodology, software, formal analysis, data curation, writing—original draft, writing—review & editing, investigation, validation, visualization. PS: conceptualization, methodology, software, formal analysis, data curation, writing—original draft, writing—review & editing. PJ: software, data curation, writing—original draft, writing—review & editing. AN: software, writing—review & editing. MZM: software, data curation, writing—original draft, writing—review & editing. GB: writing—review & editing. BK: writing—review & editing. KP: software, data curation, writing—review & editing. SA: resources, writing—review & editing. MC: writing—review & editing. RD: writing—review & editing, supervision, project administration. IKS: writing—review & editing, resources, supervision, project administration. MAS: writing—review & editing, resources, supervision, project administration.
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Khan, M.J., Singh, P., Jha, P. et al. Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS. 3 Biotech 13, 282 (2023). https://doi.org/10.1007/s13205-023-03700-1
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DOI: https://doi.org/10.1007/s13205-023-03700-1