Abstract
Sepsis-induced tissue and organ damage is caused by an overactive inflammatory response, immune dysfunction, and coagulation dysfunction. Danger-associated molecular pattern (DAMP) molecules play a critical role in the excessive inflammation observed in sepsis. In our previous research, we identified NMI as a new type of DAMP molecule that promotes inflammation in sepsis by binding to toll-like receptor 4 (TLR4) on macrophage surfaces, activating the NF-κB pathway, and releasing pro-inflammatory cytokines. However, it is still unknown whether NMI plays a significant role in other pathways. Our analysis of bulk and single-cell transcriptome data from the GEO database revealed a significant increase in NMI expression in neutrophils and monocytes in sepsis patients. It is likely that NMI functions through multiple receptors in sepsis, including IFNAR1, IFNAR2, TNFR1, TLR3, TLR1, IL9R, IL10RB, and TLR4. Furthermore, the correlation between NMI expression and the activation of NF-κB, MAPK, and JAK pathways, as well as the up-regulation of their downstream pro-inflammatory factors, demonstrates that NMI may exacerbate the inflammatory response through these signaling pathways. Finally, we demonstrated that STAT1 phosphorylation was enhanced in RAW cells upon stimulation with NMI, supporting the activation of JAK signaling pathway by NMI. Collectively, these findings shed new light on the functional mechanism of NMI in sepsis.
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Availability of Data and Materials
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. Raw and processed next-generation sequencing datasets are available for download in the NCBI Gene Expression Comprehensive Database (GEO) at numbers: GSE137340, GSE95233 and GSE57065 (bulk RNA-seq); GSE167363 (scRNA-seq).
Abbreviations
- CLRs:
-
C-type lectin receptors
- DAMP:
-
Danger-associated molecular pattern
- DEGs:
-
Differentially expressed genes
- eCIRP:
-
Extracellular cold-inducible RNA-binding protein
- GEO:
-
Gene Expression Omnibus
- GSEA:
-
Gene set enrichment analysis
- GSVA:
-
Gene set variation analysis
- HC:
-
Healthy controls
- HSPs:
-
Heat shock proteins
- HMGB1:
-
High-mobility group box protein 1
- IL-33:
-
Interleukin-33
- NCBI:
-
National Center for Biotechnology Information
- NLRs:
-
NOD-like receptors
- NMI:
-
N-myc and STAT interactor
- PAMPs:
-
Pathogen-associated molecular patterns
- PBMC:
-
Peripheral blood mononuclear cells
- PRRs:
-
Pattern recognizing receptors
- RAGE:
-
Receptor for advanced glycation end products
- RLRs:
-
RIG-like receptors
- scRNA-seq:
-
Single-cell RNA sequencing
- SIRS:
-
Systemic inflammatory response syndrome
- SVA:
-
Surrogate Variable Analysis
- TLR4:
-
Toll-like receptor 4
- TLRs:
-
Toll-like receptors
- TREM-1:
-
Triggering receptor expressed on myeloid cells-1
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Acknowledgements
We thank Prof. Huanhuan Liang (Sun Yat-sen University) for valuable discussion and critical comments on the manuscript. We also thank all the contributors of the public databases used in this study for providing all the data for analysis.
Funding
The work was supported by the grants from Shenzhen Science and technology planning project (project no. JCYJ20200109142412265, ZDSYS20220606100803007 to Y.L., project no. RCBS20200714114922284 to Z.W.; project no. 202206193000001, 20220817122906001 to J.Q.). The funding bodies were not involved in the design of the study, collection, analysis, interpretation of data, or writing of the manuscript.
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J.Z. and Z.Y. collected the data and performed all the analysis. J.Z., Z.Y., and J.S. prepared the images. J.Z., D.X., J.Q., Z.W., and Y.L. wrote the manuscript and organized the study. All authors contributed to the manuscript and approved the version as submitted.
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Zeng, J., Yang, Z., Xu, D. et al. NMI Functions as Immuno-regulatory Molecule in Sepsis by Regulating Multiple Signaling Pathways. Inflammation 47, 60–73 (2024). https://doi.org/10.1007/s10753-023-01893-4
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DOI: https://doi.org/10.1007/s10753-023-01893-4