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Lipopolysaccharide desensitizes monocytes-macrophages to CD40 ligand stimulation
Anna Sinistro1, Chiara Ciaprini, Silvia Natoli
1Department of Public Health and Cellular Biology, Chair of Infectious Diseases, University of Rome 'Tor Vergata', Rome, Italy.
Abstract:
Polymicrobial sepsis induces the suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. Here, we examined whether macrophages were refractory to only LPS or if they were unable to respond to other stimuli such as CD40 ligand (CD40L). Monocytic cells exposed in vitro to LPS showed a dose-dependent reduction of their ability to produce interleukin-12 and tumour necrosis factor-alpha upon subsequent CD40L stimulation, as compared to cells stimulated with CD40L alone. Similarly, LPS interfered with the up-regulation of CD40, CD80 and CD86 induced by CD40L in monocytic cells. The effect of LPS on the response of monocytes to CD40L was similar whether these cells were directly exposed to LPS or cocultured with LPS-pretreated cells, indicating that soluble factors released by LPS stimulation could mediate tolerance to CD40L. We also show that the functional alterations induced by LPS in monocytes can be reversed by indomethacin, thus suggesting a role for inducible cyclooxygenase in mediating the LPS-induced hyporesponsive state of monocytes to CD40L. In conclusion, we propose that in vitro CD40L tolerance may be an appropriate model of monocyte alteration observed during septic immunosuppression and may help in the development of novel therapeutic strategies.
Insights
Sepsis impairs macrophage function, making them unresponsive to stimuli like lipopolysaccharide (LPS) and CD40 ligand (CD40L). Indomethacin reversed this hyporesponsiveness, suggesting a therapeutic target for septic immunosuppression.
Area of Science:
- Immunology
- Cellular Biology
- Sepsis Pathophysiology
Background:
- Polymicrobial sepsis leads to suppressed macrophage function.
- Macrophages exhibit reduced pro-inflammatory cytokine production after LPS exposure.
- The refractory state of macrophages to LPS requires further investigation regarding other stimuli.
Purpose of the Study:
- To investigate if macrophages are refractory only to LPS or also to other stimuli like CD40 ligand (CD40L).
- To explore the mechanisms underlying LPS-induced hyporesponsiveness in monocytes.
- To identify potential therapeutic strategies for septic immunosuppression.
Main Methods:
- Monocytic cells were exposed to LPS in vitro.
- Subsequent stimulation with CD40L was performed to assess cytokine production (IL-12, TNF-alpha) and co-stimulatory molecule expression (CD40, CD80, CD86).
- The role of soluble factors and indomethacin was evaluated.
Main Results:
- LPS exposure dose-dependently reduced IL-12 and TNF-alpha production upon subsequent CD40L stimulation.
- LPS interfered with CD40L-induced upregulation of CD40, CD80, and CD86.
- Soluble factors from LPS-stimulated cells mediated tolerance to CD40L, and indomethacin reversed LPS-induced hyporesponsiveness.
Conclusions:
- In vitro CD40L tolerance serves as a model for monocyte alterations during septic immunosuppression.
- Inducible cyclooxygenase plays a role in LPS-induced hyporesponsiveness.
- This model may aid in developing novel therapeutic strategies for sepsis.
