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NMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury
Zhikai Xiahou1,2, Xiangli Wang1,2, Juan Shen1,2
1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Abstract:
Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Identifying DAMPs and revealing their functions are thus of crucial importance. Here we report that two molecules, N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs and are released by activated macrophages during lipopolysaccharide-induced septic shock or acetaminophen-induced liver injury. We show that extracellular NMI and IFP35 activate macrophages to release proinflammatory cytokines by activating nuclear factor-κB through the Toll-like receptor 4 pathway. In addition, the serum levels of NMI are increased in patients who succumbed to severe inflammation. NMI deficiency reduces inflammatory responses and mortality in mouse models of sepsis and liver injury. We therefore propose that extracellular NMI and IFP35 exacerbate inflammation as DAMPs, making them potential therapeutic targets for clinical intervention.Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.
Insights
Two novel damage-associated molecular patterns (DAMPs), N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35), promote inflammation by activating macrophages. Targeting these DAMPs may offer new therapeutic strategies for inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Damage-associated molecular patterns (DAMPs) are crucial mediators of innate immunity, inflammation, and cellular damage.
- Identifying novel DAMPs and understanding their functions are vital for developing therapeutic interventions.
Purpose of the Study:
- To identify novel DAMPs involved in inflammatory responses.
- To elucidate the mechanisms by which these DAMPs activate immune cells and exacerbate inflammation.
Main Methods:
- Investigated the role of N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) as DAMPs.
- Utilized mouse models of septic shock and acetaminophen-induced liver injury.
- Analyzed macrophage activation, cytokine release, and the Toll-like receptor 4 (TLR4)/NF-κB pathway.
Main Results:
- Extracellular NMI and IFP35 were released by activated macrophages during sepsis and liver injury.
- NMI and IFP35 activated macrophages via TLR4 and NF-κB, leading to pro-inflammatory cytokine release.
- Serum NMI levels correlated with severe inflammation, and NMI deficiency reduced mortality in disease models.
Conclusions:
- NMI and IFP35 function as DAMPs that exacerbate inflammation by activating macrophages.
- These molecules represent potential therapeutic targets for managing inflammatory conditions.
- Targeting extracellular NMI and IFP35 could mitigate sepsis and liver injury outcomes.