GO:0072573 tolerance induction to lipopolysaccharide: Innate Immune Reprogramming, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0072573 tolerance induction to lipopolysaccharide describes the biological process by which cells or organisms become hyporesponsive to LPS after prior exposure, a phenomenon also called endotoxin tolerance.
• Macrophages are central mediators of LPS tolerance, and their functional reprogramming is required for protection against LPS/D-galactosamine lethality in vivo.
• CD14 is a key receptor whose modulation is biochemically and functionally linked to the tolerant state.
• The itaconate pathway acts as a central regulatory node that links innate immune tolerance to trained immunity, integrating metabolic and epigenetic rewiring.
• miR-146a induction by a cyanobacterial LPS antagonist mediates endotoxin cross-tolerance, showing that non-coding RNAs participate in tolerance induction.
• Tolerance induction to LPS is relevant to sepsis, chronic inflammation, vaccine design, and immunotherapy because it reprograms myeloid and lymphoid cells [5,8].
Description
Tolerance induction to lipopolysaccharide (GO:0072573) is the biological process by which a cell or organism becomes specifically hyporesponsive to lipopolysaccharide (LPS, also called endotoxin) after an initial exposure or after exposure to a cross-tolerizing stimulus. This process is a fundamental homeostatic mechanism of the innate immune system, preventing excessive inflammatory damage during sustained or repeated microbial challenge. It is distinct from general immunosuppression because it is directed at LPS antigens and involves active reprogramming of signaling, metabolism, and gene expression [2,3]. Researchers study GO:0072573 because it shapes outcomes in sepsis, chronic inflammatory diseases, and cancer immunotherapy, and because it intersects with trained immunity and epigenetic memory [2,5]. The process is experimentally tractable: pretreatment with LPS protects against LPS/D-galactosamine lethality in a macrophage-dependent manner, providing a classical in vivo model of tolerance. At the molecular level, tolerance involves altered expression of receptors such as CD14, changes in intracellular signaling, and induction of regulatory non-coding RNAs such as miR-146a [1,7]. Because tolerance can be induced by structurally related or unrelated LPS antagonists, cross-tolerance is an important feature of the process. Understanding GO:0072573 therefore requires integrating receptor biology, metabolic rewiring, and epigenetic regulation [2,3,7].
tolerance induction to lipopolysaccharide At A Glance
| GO ID | GO:0072573 |
|---|---|
| GO term | tolerance induction to lipopolysaccharide |
| Ontology | biological_process |
| Synonym | tolerance induction to endotoxin; tolerance induction to LPS |
| Major function | Induction of a hyporesponsive state specifically directed at lipopolysaccharide antigens |
| Primary cell types | Monocytes, macrophages, microglia, dendritic cells, and other innate immune cells [3,4,6] |
| Key receptors | CD14 and associated LPS-sensing machinery |
| Key regulatory nodes | Itaconate pathway, miR-146a, epigenetic and metabolic rewiring [1,2,8] |
| Physiological relevance | Limits inflammatory damage during repeated or sustained LPS exposure |
What Is GO:0072573?
In plain terms, GO:0072573 describes how a cell that has seen LPS before becomes less responsive to it the next time. The QuickGO definition states that it is tolerance induction directed at lipopolysaccharide antigens. This means the process is antigen-directed: the tolerant state is specifically aimed at LPS rather than being a blanket shutdown of all immune responses. Synonyms include tolerance induction to endotoxin and tolerance induction to LPS. The process is best documented in monocytes and macrophages, where prior LPS exposure reprograms cytokine production, signaling, and metabolism [2,3,4].
Why Is tolerance induction to lipopolysaccharide Important in Cell Biology?
GO:0072573 matters because LPS tolerance is a double-edged sword in human health. On one hand, it protects the host from lethal endotoxin shock, as shown by the macrophage-dependent protection against LPS/D-galactosamine lethality after LPS pretreatment. On the other hand, the same reprogramming can render patients transiently immunocompromised, contributing to secondary infections in sepsis and to altered vaccine responses [3,5]. The process is also mechanistically informative: it reveals how innate immune cells store a memory of prior stimulation through metabolic and epigenetic changes, a concept that bridges tolerance and trained immunity. Because tolerance can be induced by non-canonical LPS antagonists and by allergen-derived reprogramming agents, it has translational implications for immunotherapy and allergy [1,8].
• Protects against lethal endotoxin shock in experimental models through macrophage-dependent mechanisms.
• Contributes to the immunosuppressive phase of sepsis and increases susceptibility to secondary infection.
• Serves as a paradigm for innate immune memory and its intersection with trained immunity.
• Involves CD14 downregulation or functional modulation, linking receptor biology to tolerance.
• Is mediated in part by miR-146a, connecting non-coding RNA networks to endotoxin cross-tolerance.
• Can be induced by cyanobacterial LPS antagonists, expanding the range of tolerance-inducing agents.
• Is relevant to neuroinflammation because microglia and astrocytes show sequential cytokine reprogramming after systemic immune challenge.
• Has implications for vaccine design and immunotherapy because tolerogenic dendritic cells can be generated by metabolic and epigenetic rewiring.
• Provides a model for studying how tissue CD8+ T cells are reprogrammed by myeloid cells and modulated by LPS.
• Offers a tractable system for CRISPR screens of negative regulators of LPS signaling and tolerance.
What Happens During tolerance induction to lipopolysaccharide?
Initial LPS sensing and receptor engagement
In simple terms: The cell first detects LPS through its surface receptors, which starts the whole tolerance program.
Tolerance induction begins when LPS engages the CD14-dependent sensing machinery on monocytes and macrophages. CD14 is a glycosylphosphatidylinositol-anchored receptor that presents LPS to the TLR4/MD-2 complex, and its biochemical status changes during tolerance. In vivo, macrophages are required for the induction of tolerance to LPS/D-galactosamine lethality, indicating that the initial sensing step occurs in these cells. The strength and duration of this first signal determine whether the cell enters a tolerant state or a trained state.
Metabolic rewiring and itaconate accumulation
In simple terms: The cell changes its metabolism, and a metabolite called itaconate helps lock in the tolerant state.
The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. After LPS exposure, changes in the tricarboxylic acid cycle and itaconate production contribute to the reprogramming of cytokine responses. This metabolic rewiring is not merely a consequence of tolerance but actively shapes the epigenetic landscape that maintains hyporesponsiveness. The same pathway can also support trained immunity under different conditions, illustrating the plasticity of the response.
Epigenetic and transcriptional reprogramming
In simple terms: The cell changes which genes can be turned on later, effectively storing a memory of the first LPS encounter.
Tolerance involves stable changes in chromatin accessibility and transcription factor activity that suppress pro-inflammatory genes while preserving or enhancing anti-inflammatory and antimicrobial programs [2,3]. Allergoid-mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring, demonstrating that similar mechanisms can be harnessed pharmacologically. These epigenetic marks help explain why tolerance persists after the initial LPS stimulus is cleared [2,3].
Non-coding RNA regulation and cross-tolerance
In simple terms: Small RNA molecules such as miR-146a help the cell become tolerant even to related but distinct LPS molecules.
miR-146a induction by a cyanobacterial LPS antagonist (CyP) mediates endotoxin cross-tolerance, showing that non-coding RNAs are integral to the tolerant state. Cross-tolerance means that exposure to one LPS-like molecule can reduce responsiveness to another, broadening the biological impact of GO:0072573. This layer of regulation provides additional targets for experimental manipulation and therapeutic intervention.
Cellular crosstalk and tissue-level tolerance
In simple terms: Tolerance is not just a single-cell event; immune cells communicate with each other and with tissue cells to set the overall response.
Tissue CD14+CD8+ T cells are reprogrammed by myeloid cells and modulated by LPS, indicating that tolerance involves intercellular communication beyond monocytes and macrophages. In the central nervous system, sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge, showing that tolerance-like reprogramming occurs across glial cell types. These tissue-level interactions determine the net inflammatory outcome of repeated LPS exposure [5,6].
Key Genes Involved in GO:0072573 tolerance induction to lipopolysaccharide
The following genes and proteins are experimentally implicated in tolerance induction to lipopolysaccharide and related innate immune reprogramming.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CD14 | LPS co-receptor; its biochemical and functional status is linked to tolerance | Target for studying receptor-level tolerance mechanisms |
| TLR4 | Core LPS sensor upstream of tolerance-associated signaling | Central node for KO and point-mutation studies of LPS responsiveness |
| MYD88 | Adaptor protein in TLR4 signaling; modulates tolerance induction | Common KO target to dissect signaling branches |
| IRAK4 | Kinase in the TLR/IL-1R pathway; participates in tolerance signaling | Candidate for point-mutation studies of kinase activity |
| IRAK1 | Negative regulator of TLR signaling implicated in tolerance | KO models to test its role in hyporesponsiveness |
| TRAF6 | E3 ubiquitin ligase in TLR signaling; contributes to tolerance | Knock-in and KO models for signaling rewiring |
| NFKB1 | Transcription factor controlling pro-inflammatory gene expression | Reporter and KO models for tolerance-associated transcription |
| RELA | NF-kB subunit; its activity is altered in tolerant cells | Overexpression and KO studies of inflammatory output |
| IRF3 | Transcription factor in TRIF-dependent signaling | KO models to separate MyD88- and TRIF-dependent tolerance |
| IRF5 | Promotes pro-inflammatory responses and opposes tolerance | Overexpression models to break tolerance |
| SOCS1 | Negative regulator of cytokine signaling; induced during tolerance | Knock-in reporters to track tolerance onset |
| SOCS3 | Suppressor of cytokine signaling; modulates LPS responses | KO and point-mutation models |
| TNFAIP3 | A20; negative feedback regulator of NF-kB in LPS signaling | KO models to test tolerance maintenance |
| NFKBIA | IkB-alpha; controls NF-kB dynamics during tolerance | Point-mutation models of degradation-resistant IkB |
| MIR146A | Non-coding RNA mediating endotoxin cross-tolerance | Overexpression and KO models of miRNA-mediated tolerance |
| ACOD1 | Itaconate-producing enzyme linking metabolism to tolerance | KO and knock-in models of metabolic rewiring |
| IRG1 | Alternative name for ACOD1; itaconate pathway node | Metabolic and epigenetic studies of tolerance |
| CD8A | Marker of T cells reprogrammed by myeloid cells and LPS | Lineage-tracing and KO models of T-cell reprogramming |
How Is tolerance induction to lipopolysaccharide Regulated?
Tolerance induction to lipopolysaccharide is regulated at multiple levels. The itaconate pathway acts as a central regulatory node that links innate immune tolerance and trained immunity, integrating metabolic flux with epigenetic changes. miR-146a provides post-transcriptional regulation and mediates cross-tolerance induced by a cyanobacterial LPS antagonist. CD14 modulation is a receptor-level regulatory event that correlates with the tolerant state. Negative feedback regulators such as SOCS proteins and A20 (TNFAIP3) help maintain hyporesponsiveness after the initial stimulus, although their precise contributions vary by cell type and model. Allergoid-mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring, showing that tolerance-like states can be pharmacologically regulated. Together, these layers ensure that tolerance is inducible, reversible, and context-dependent [2,3,7].
tolerance induction to lipopolysaccharide and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CD14 | Sepsis and endotoxin tolerance | CD14 KO and knock-in monocytes/macrophages |
| ACOD1 | Metabolic control of tolerance and trained immunity | Acod1 KO mice and overexpression cell lines |
| MIR146A | Endotoxin cross-tolerance | miR-146a KO and overexpression models |
| CD8A | T-cell reprogramming by myeloid cells and LPS | CD8+ T-cell lineage-tracing and KO models |
| TNFAIP3 | Negative regulation of LPS signaling and tolerance | A20 KO and point-mutation models |
Sepsis and endotoxin shock
LPS tolerance protects against LPS/D-galactosamine lethality in a macrophage-dependent manner, making it a key adaptive response in endotoxemia. However, the same reprogramming can contribute to the immunosuppressive phase of sepsis and increase susceptibility to secondary infections. Understanding GO:0072573 is therefore central to designing therapies that preserve protective tolerance while avoiding harmful immunosuppression [3,4].
Neuroinflammation and glial reprogramming
Systemic immune challenge triggers sequential activation of microglia and astrocyte cytokine expression before overt changes in Iba-1 or GFAP immunoreactivity, indicating that tolerance-like reprogramming occurs in the brain. This has implications for neurodegenerative and neuroinflammatory conditions in which repeated peripheral LPS exposure modulates central nervous system inflammation.
Allergy and tolerogenic immunotherapy
Allergoid-mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring, linking LPS tolerance mechanisms to allergy treatment. This suggests that the pathways underlying GO:0072573 can be harnessed to induce antigen-specific tolerance in allergic disease.
T-cell reprogramming and cancer immunotherapy
Tissue CD14+CD8+ T cells are reprogrammed by myeloid cells and modulated by LPS, showing that tolerance induction extends to lymphoid compartments. This crosstalk may influence antitumor immunity and the design of LPS-based adjuvants in cancer immunotherapy.
From tolerance induction to lipopolysaccharide-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is gene X required for LPS tolerance induction? | CRISPR knockout in macrophages followed by LPS pretreatment and rechallenge |
| Does a specific phosphorylation site control tolerance? | Point-mutation knock-in of the phospho-site in the endogenous locus |
| Does overexpression of gene X break tolerance? | CRISPRa or lentiviral overexpression in monocytes |
| Where is the protein localized during tolerance? | Endogenous tagged knock-in with fluorescent tag |
| Which metabolic genes regulate tolerance? | CRISPR library screening under LPS tolerance conditions |
| How does gene X affect cross-tolerance? | miR-146a or CyP-induced cross-tolerance model with KO cells |
How to Study the tolerance induction to lipopolysaccharide Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional changes during tolerance | Identify tolerance-associated gene programs |
| ATAC-seq | Chromatin accessibility | Map epigenetic rewiring in tolerant cells |
| Metabolomics | Itaconate and TCA cycle intermediates | Link metabolism to tolerance |
| ELISA/multiplex | Cytokine production after rechallenge | Functional validation of tolerance [3,4] |
| Immunohistochemistry | Iba-1 and GFAP expression | Assess glial reprogramming in vivo |
| Flow cytometry | Surface markers such as CD14 and CD8 | Track receptor and T-cell changes [5,7] |
| CRISPR screening | Gene requirements for tolerance | Discover novel regulators of GO:0072573 |
Transcriptomic and epigenetic profiling
RNA-seq and ATAC-seq before and after LPS rechallenge reveal the transcriptional and chromatin changes that define tolerance [2,8]. These methods identify genes whose expression is suppressed or enhanced in the tolerant state and can be combined with CRISPR perturbations.
Metabolic and flux analysis
Metabolomics and flux analysis measure itaconate and related TCA cycle intermediates that regulate tolerance and trained immunity. Such approaches link metabolic rewiring to functional outcomes in macrophages and dendritic cells.
Cytokine and functional readouts
ELISA and multiplex cytokine assays quantify TNF and other cytokines after LPS rechallenge, providing a direct functional measure of tolerance [3,4]. These readouts are standard in macrophage and monocyte tolerance models [3,4].
Imaging and glial activation markers
Immunohistochemistry for Iba-1 and GFAP, combined with cytokine measurements, assesses tolerance-like reprogramming in the brain after systemic immune challenge. Imaging can also track tagged proteins in knock-in models.
How CRISPR Can Be Used to Study GO:0072573 tolerance induction to lipopolysaccharide
Knockout
CRISPR knockout of candidate genes such as CD14, ACOD1, or TNFAIP3 in macrophages allows direct testing of their requirement for tolerance induction [2,7]. KO cells can be pretreated with LPS and rechallenged to measure cytokine output and confirm loss or gain of tolerance [3,4].
Point Mutation
Point-mutation knock-in of phosphorylation sites or catalytic residues in kinases such as IRAK4 or in NFKBIA enables precise dissection of signaling events that maintain tolerance. These models avoid confounding effects of complete gene loss and reveal dynamic regulation.
Knock-in
Endogenous tagged knock-in of CD14 or other tolerance-associated proteins permits real-time tracking of localization and interactions during tolerance induction. Reporter knock-in of cytokine loci can also provide sensitive readouts of the tolerant state.
Overexpression
CRISPRa or lentiviral overexpression of miR-146a, ACOD1, or SOCS1 can test whether increasing their levels is sufficient to induce or enhance tolerance [1,2]. Overexpression models are particularly useful for non-coding RNAs and negative regulators.
How EDITGENE Supports tolerance induction to lipopolysaccharide Research
Researchers studying tolerance induction to lipopolysaccharide-related genes often need to determine whether a candidate gene is causally involved in the tolerant state or merely correlated with it. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for tolerance induction to lipopolysaccharide research.
Frequently Asked Questions About tolerance induction to lipopolysaccharide
What is tolerance induction to lipopolysaccharide (GO:0072573)?
It is the biological process by which a cell or organism becomes hyporesponsive specifically to lipopolysaccharide after prior exposure, as defined by GO:0072573.
What genes are involved in tolerance induction to lipopolysaccharide?
Key genes include CD14, TLR4, MYD88, IRAK4, TNFAIP3, ACOD1, and MIR146A, among others [1,2,7].
How is LPS tolerance different from trained immunity?
Both involve innate immune memory, but tolerance leads to hyporesponsiveness while trained immunity enhances responses; the itaconate pathway links the two.
Which cells mediate LPS tolerance?
Macrophages are central mediators, and microglia, astrocytes, dendritic cells, and CD8+ T cells also participate [4,5,6,8].
What is the role of CD14 in LPS tolerance?
CD14 is an LPS co-receptor whose biochemical and functional status is linked to the tolerant state.
Can non-coding RNAs regulate LPS tolerance?
Yes, miR-146a induction by a cyanobacterial LPS antagonist mediates endotoxin cross-tolerance.
What experimental models are used to study LPS tolerance?
Common models include LPS pretreatment followed by rechallenge in macrophages, and LPS/D-galactosamine lethality protection assays in mice [3,4].
How does metabolism influence LPS tolerance?
The itaconate pathway acts as a central regulatory node linking innate immune tolerance and trained immunity through metabolic and epigenetic rewiring.
Is LPS tolerance relevant to human disease?
Yes, it is relevant to sepsis, neuroinflammation, allergy, and cancer immunotherapy [3,5,6,8].
How can CRISPR help study tolerance induction to lipopolysaccharide?
CRISPR knockout, knock-in, point mutation, and overexpression models allow causal testing of candidate genes in tolerance assays [1,2,7].
Conclusion
GO:0072573 tolerance induction to lipopolysaccharide is a fundamental innate immune process that reprograms cells to become hyporesponsive to endotoxin. It is mediated by receptor-level changes, metabolic rewiring through the itaconate pathway, epigenetic modifications, and non-coding RNAs such as miR-146a [1,2,7]. The process protects against lethal endotoxin shock but also contributes to immunosuppression in sepsis and shapes neuroinflammation and immunotherapy responses [3,4,6,8]. CRISPR-based models are powerful tools for dissecting the causal genes and pathways that control this process. EDITGENE provides comprehensive CRISPR services to support discovery and validation in this field.
References
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- 2. Domínguez-Andrés J et al.. 2019. The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity.. Cell Metab 29(1):211-220.e5 PMID: 30293776
- 3. Ziegler-Heitbrock HW. 1995. Molecular mechanism in tolerance to lipopolysaccharide.. J Inflamm 45(1):13-26 PMID: 7583350
- 4. Freudenberg MA et al.. 1988. Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages.. Infect Immun 56(5):1352-7 PMID: 3356468
- 5. Pallett LJ et al.. 2023. Tissue CD14(+)CD8(+) T cells reprogrammed by myeloid cells and modulated by LPS.. Nature 614(7947):334-342 PMID: 36697826
- 6. Norden DM et al.. 2016. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.. Glia 64(2):300-16 PMID: 26470014
- 7. Labeta MO et al.. 1993. CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis.. Immunology 80(3):415-23 PMID: 7507090
- 8. Benito-Villalvilla C et al.. 2022. Allergoid-mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring.. J Allergy Clin Immunol 149(1):212-222.e9 PMID: 34153371
