Endotoxin Tolerance in Innate Immune Responses

Endotoxin tolerance describes a reprogrammed state of innate immune cells, notably monocytes and macrophages, in which a prior encounter with bacterial lipopolysaccharide (LPS) leads to a selectively blunted inflammatory response upon re-exposure. This adaptation limits the production of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-6, thereby protecting host tissues from collateral damage during persistent or repeated infections. Mechanistically, tolerance involves alterations in receptor signalling, chromatin accessibility and metabolic pathways, yielding a hybrid activation state that retains anti-microbial functions while suppressing excessive inflammation. Clinically, endotoxin tolerance underlies the immunosuppressed phase of sepsis and contributes to vulnerability to secondary infections, but also offers a model for therapeutic modulation of overzealous inflammation in conditions such as septic shock and sterile injury.

Research from Nature Portfolio

A foundational study demonstrated that interferon β confers protection against lethal endotoxic and septic shock by upregulating the deacetylase SIRT1 in macrophages. Enhanced SIRT1 activity deacetylates NF-κB, reducing transcription of key pro-inflammatory cytokines in response to LPS. In vivo, systemic interferon β markedly improved survival in mouse models of endotoxaemia and bacterial sepsis; this benefit was lost when SIRT1 function was inhibited. These findings identify the interferon β–SIRT1 axis as a molecular switch in endotoxin tolerance and inspire strategies to harness innate immune reprogramming for sepsis therapy.

Endotoxin Tolerance in Innate Immune Responses publication trend

The graph below shows the total number of articles in endotoxin tolerance in innate immune responses across all publications each year (not limited to Nature Index journals).

Technical terms

Endotoxin Tolerance: A hypo-responsive state of innate immune cells following an initial LPS exposure, characterised by reduced pro-inflammatory cytokine production.

Lipopolysaccharide (LPS): A glycolipid component of Gram-negative bacterial cell walls recognised by toll-like receptor 4 to activate innate immunity.

Toll-Like Receptor 4 (TLR4): A pattern recognition receptor that binds LPS and triggers signalling cascades leading to cytokine gene expression.

SIRT1: An NAD-dependent deacetylase that modulates transcription factors such as NF-κB, thereby regulating inflammatory gene programmes in macrophages.

Monocytic Myeloid-Derived Suppressor Cells (M-MDSCs): A population of immature myeloid cells that expand under chronic inflammatory conditions and suppress immune responses via metabolic and signalling mechanisms.

References

1. Interferon β protects against lethal endotoxic and septic shock through SIRT1 upregulation. Scientific Reports (2014).
2. Single cell RNA-seq reveals cellular and transcriptional heterogeneity in the splenic CD11b+Ly6Chigh monocyte population expanded in sepsis-surviving mice. Molecular Medicine (2024).
3. Induction of endotoxin tolerance in murine monocyte and macrophage cell populations – optimal LPS dose and compartment-specific reversal by β-glucan. Food & Function (2025).