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Differential response induced by LPS and MPLA in immunocompetent and septic individuals
Chloé Albert Vega1, Eleni Karakike2, François Bartolo3
1Joint Research Unit Hospices Civils de Lyon-bioMérieux, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, 69495 Lyon, France.
Abstract:
Lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) induce, overall, similar transcriptional profiles in healthy individuals, although LPS has been shown to more potently induce pro-inflammatory cytokines. We explore herein whether MPLA could be considered as a synthetic replacement of LPS in immune functional assays to study anergy of immune cells in septic patients. Ex vivo whole blood stimulation with MPLA revealed a lower induction of the TNFα secreted protein in 20 septic patients (SP) compared to 10 healthy volunteers (HV), in agreement with monocyte anergy. Principal component analysis of the 93-gene molecular response to MPLA and LPS stimulation found that the main variability was driven by stimulation in HV and by pathophysiology in SP. MPLA was a stronger inducer of the HLA family genes than LPS in both populations, arguing for divergent signalling pathways downstream of TLR-4. In addition, MPLA appeared to present a more informative stratification potential within the septic population.
Insights
Monophosphoryl lipid A (MPLA) can serve as a safer alternative to lipopolysaccharide (LPS) for studying immune anergy in sepsis. MPLA shows distinct immune responses, offering better patient stratification than LPS.
Area of Science:
- Immunology
- Molecular Biology
- Sepsis Pathophysiology
Background:
- Lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) are Toll-like receptor 4 (TLR-4) agonists with distinct immune-modulating properties.
- LPS is a potent inducer of pro-inflammatory cytokines, while MPLA exhibits a generally weaker, yet distinct, immune response.
- Understanding immune cell anergy in sepsis is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate whether MPLA can be used as a synthetic substitute for LPS in immune functional assays to study immune cell anergy in septic patients.
- To compare the molecular and protein-level responses to MPLA and LPS stimulation in both healthy volunteers and septic patients.
- To explore the potential of MPLA in stratifying septic patients based on their immune response.
Main Methods:
- Ex vivo whole blood stimulation assays using MPLA and LPS.
- Measurement of TNFα secreted protein levels.
- 93-gene molecular response profiling via principal component analysis (PCA).
- Comparison of immune responses between 20 septic patients (SP) and 10 healthy volunteers (HV).
Main Results:
- MPLA induced lower TNFα secretion in septic patients compared to healthy volunteers, consistent with monocyte anergy.
- Principal component analysis revealed that immune cell stimulation was the primary driver of variability in healthy volunteers, while pathophysiology dominated in septic patients.
- MPLA demonstrated a stronger induction of HLA family genes than LPS in both groups, suggesting different downstream signaling pathways.
- MPLA exhibited a greater potential for stratifying septic patients compared to LPS.
Conclusions:
- MPLA can be considered a valuable tool for studying immune anergy in sepsis, offering a potentially safer alternative to LPS.
- MPLA elicits distinct transcriptional and signaling pathway activation compared to LPS, particularly regarding HLA gene induction.
- MPLA holds promise for improving patient stratification within the septic population based on molecular immune profiles.
