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Published on: May 31, 2018
Semaphorin 3E Regulates the Response of Macrophages to Lipopolysaccharide-Induced Systemic Inflammation
Ashfaque Mohammed1, Ifeoma Okwor1, Lianyu Shan1
1Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
Abstract:
Semaphorin 3E (Sema3E) is a secreted protein that was initially discovered as a neuronal guidance cue. Recent evidence showed that Sema3E plays an essential role in regulating the activities of various immune cells. However, the exact role of Sema3E in macrophage function, particularly during inflammation, is not fully understood. We studied the impact of Sema3E gene deletion on macrophage function during the LPS-induced acute inflammatory response. We found that Sema3E-deficient (Sema3e ) mice were better protected from LPS-induced acute inflammation as exemplified by their superior clinical score and effective temperature control compared with their wild-type littermates. This superior control of inflammatory response in Sema3e mice was associated with significantly lower phosphorylation of ERK1/2, AKT, STAT3, and NF-κB, and a concomitant reduction in inducible NO synthase expression and production of TNF and IL-6 compared with their Sema3e littermates. Sema3e mice also contained significantly higher numbers of activated macrophages compared with their Sema3e littermates at both baselines and after LPS challenge. In vivo-specific deletion of the Sema3E high-affinity receptor, plexinD1, on macrophages led to the improvement in clinical disease following exposure to a lethal dose of LPS. Collectively, our data show that Sema3E plays an essential role in dampening the early inflammatory response to LPS by regulating macrophage function, suggesting an essential role of this pathway in macrophage inflammatory response.
Insights
Semaphorin 3E (Sema3E) deficiency protects mice from acute inflammation by enhancing macrophage function. This study reveals Sema3E
Area of Science:
- Immunology
- Cell Biology
- Neuroscience
Background:
- Semaphorin 3E (Sema3E), initially identified as a neuronal guidance cue, is increasingly recognized for its role in immune cell regulation.
- The precise function of Sema3E in macrophage activity during inflammatory conditions remains incompletely elucidated.
Purpose of the Study:
- To investigate the role of Sema3E in modulating macrophage function during lipopolysaccharide (LPS)-induced acute inflammation.
- To determine the impact of Sema3E gene deletion on the inflammatory response and macrophage activation.
Main Methods:
- Utilized Sema3E-deficient (Sema3e) mice and wild-type littermates exposed to LPS to induce acute inflammation.
- Assessed clinical outcomes, body temperature, inflammatory signaling pathways (ERK1/2, AKT, STAT3, NF-κB), and inflammatory mediator production (iNOS, TNF, IL-6).
- Investigated the role of plexinD1, the Sema3E receptor, through in vivo-specific deletion on macrophages.
Main Results:
- Sema3e mice exhibited enhanced protection against LPS-induced inflammation, characterized by improved clinical scores and temperature regulation.
- Reduced phosphorylation of key inflammatory signaling molecules (ERK1/2, AKT, STAT3, NF-κB) and decreased production of TNF and IL-6 were observed in Sema3e mice.
- Sema3e mice displayed significantly higher numbers of activated macrophages at baseline and post-LPS challenge.
- In vivo deletion of plexinD1 on macrophages improved clinical outcomes following lethal LPS exposure.
Conclusions:
- Sema3E plays a critical role in regulating macrophage function during the early stages of LPS-induced inflammation.
- The Sema3E pathway is essential for modulating the inflammatory response mediated by macrophages.
- Targeting the Sema3E-plexinD1 axis presents a potential therapeutic strategy for inflammatory diseases.
