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Published on: May 31, 2018
Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation
Young Jun Kang1, Jianming Chen, Motoyuki Otsuka
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
The activation of p38alpha, a MAPK family member, is associated with macrophage activation by microbial pattern molecules, such as LPS. The requirement of p38alpha in inflammatory responses has been shown in a number of studies using chemical inhibitors, though the inhibitors also inhibit p38beta and perhaps some other enzymes. In this study, we used conditional knockout of p38alpha in macrophages to address the role of p38alpha in macrophage activation. We found that p38alpha deficiency causes a significant inhibition in the production of LPS-induced TNF-alpha, IL-12, and IL-18, but it has little or no effect on IL-6 or IFN-beta production. Knockout of p38alpha in macrophages did not affect LPS-induced activation of the other major signaling pathways (NF-kappaB, Jnk, and Erk), nor did it affect the transcriptional activity of NF-kappaB. It had little inhibitory effect on LPS-induced AP-1 activity, but it significantly inhibited LPS-induced C/EBP-beta and CREB activation, indicating that the role of p38alpha in cytokine production in macrophages is at least in part through its regulation of C/EBP-beta and CREB activation. In addition, we also confirmed that p38alpha is important for phagocytosis of bacteria by macrophages. Our in vivo studies with two murine models showed that p38alpha is involved in sepsis. Collectively, our data demonstrate that p38alpha is an important player in inflammatory responses.
Insights
p38alpha activation is crucial for macrophage inflammatory responses, regulating key cytokine production and bacterial phagocytosis. This study clarifies its specific role in inflammation and sepsis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- p38alpha, a mitogen-activated protein kinase (MAPK), is implicated in macrophage activation by microbial molecules like lipopolysaccharide (LPS).
- Previous studies using chemical inhibitors showed p38alpha's role in inflammation, but these inhibitors lacked specificity, affecting other enzymes.
- Conditional knockout models are essential for precisely defining p38alpha's function in macrophages.
Purpose of the Study:
- To elucidate the specific role of p38alpha in macrophage activation and inflammatory responses.
- To investigate the downstream signaling pathways regulated by p38alpha in response to LPS.
- To assess the in vivo relevance of p38alpha in inflammatory conditions like sepsis.
Main Methods:
- Utilized conditional knockout mice to specifically delete p38alpha in macrophages.
- Stimulated macrophages with LPS and measured the production of various cytokines (TNF-alpha, IL-12, IL-18, IL-6, IFN-beta).
- Assessed the activation of key signaling pathways (NF-kappaB, Jnk, Erk, AP-1, C/EBP-beta, CREB) and bacterial phagocytosis.
Main Results:
- p38alpha deficiency significantly inhibited LPS-induced production of TNF-alpha, IL-12, and IL-18, but not IL-6 or IFN-beta.
- LPS-induced activation of NF-kappaB, Jnk, and Erk pathways remained unaffected by p38alpha knockout.
- p38alpha knockout significantly inhibited LPS-induced C/EBP-beta and CREB activation, and impaired bacterial phagocytosis.
- In vivo studies indicated p38alpha's involvement in murine models of sepsis.
Conclusions:
- p38alpha plays a critical, specific role in LPS-induced cytokine production by macrophages, primarily via C/EBP-beta and CREB.
- p38alpha is essential for macrophage phagocytosis and contributes to the inflammatory response in sepsis.
- Targeting p38alpha may offer therapeutic potential for inflammatory diseases.
