UNDERSTANDING THE INFLAMMASOME SIGNALING PATHWAY

The inflammasome signaling pathway is a critical component of the innate immune response. It detects microbial infections, cellular stress, or tissue damage, leading to the activation of inflammatory responses. Multiprotein complexes within this network, such as NLRP3 assemblies, activate caspase-1, which drives the maturation of pro-inflammatory cytokines like IL-1β and IL-18. Imbalances in this signaling are linked to various inflammatory and autoimmune diseases, including arthritis, diabetes, and neurodegenerative disorders.

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Illustration of the NLRP3 inflammasome mechanism of activation, highlighting key steps such as priming, sensing, oligomerization, and cytokine release

Mechanism of NLRP3 inflammasome activation.

KEY COMPONENTS OF INFLAMMASOME PATHWAY

The molecular assemblies driving immune signaling typically include:

Sensors: Receptors like NLRP3, NLRC4, AIM2, and Pyrin that detect microbial or damage-associated signals.
Adaptor Proteins: ASC links these receptors to caspase-1, forming active signaling complexes.
Caspase-1: An enzyme that activates cytokines (IL-1β, IL-18) and induces pyroptosis.
Cytokines: IL-1β and IL-18 mediate inflammation and immune activation.
Gasdermin D: Forms membrane pores for cytokine release and cell death.
Stimuli: Includes signals such as ATP, reactive oxygen species (ROS), or microbial toxins.

ACTIVATION MECHANISMS

Inflammasome activation generally occurs in two main signals:

Priming Signal: Triggered by PAMPs or DAMPs through Toll-like receptors (TLRs), leading to the transcriptional upregulation of inflammasome components such as NLRP3, caspase-1, pro-IL-1β, and pro-IL-18.
Activation Signal: This signal can arise from various stimuli, including potassium efflux, lysosomal damage, or other cellular stressors. For example, in the case of NLRP3, specific triggers like ATP or uric acid can lead to its oligomerization and subsequent recruitment of ASC and caspase-1.

The activation process can be summarized in four key steps:

Priming: Induction of transcriptional changes in response to initial signals.
Sensing: Detection of secondary signals that indicate cellular distress.
Oligomerization: Formation of large complexes involving ASC and caspase-1.
Cytokine Release: Secretion of active IL-1β and IL-18 into the extracellular space, initiating inflammatory responses.

DISEASES ASSOCIATIONS

Imbalances in this signaling network are tied to numerous diseases:

Inflammatory Diseases: Conditions like Gout, rheumatoid arthritis, and Crohn's disease.
Metabolic Disorders: Obesity and type 2 diabetes due to chronic low-grade inflammation.
Neurodegenerative Diseases: Overactivity contributes to Alzheimer’s and Parkinson’s.
Cardiovascular Diseases: Includes atherosclerosis and myocardial infarction.

CLINICAL RELEVANCE

Dysregulation of this immune signaling pathways has been implicated in several diseases, including autoimmune disorders, metabolic syndromes, and cancer. For instance:

Cancer: This pathway can influence tumor growth and immune evasion by modulating immune checkpoints like PD-L1.
Autoimmune Diseases: Conditions such as sarcoidosis exhibit upregulated NLRP3 activity, suggesting potential therapeutic targets within this signaling pathway.

(1) Sharma BR, Kanneganti TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol. (2021);22(5):550-559.

(2) Paik S et al. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. (2021);18(5):1141-1160.

(3) Wang L, Hauenstein AV. The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med. (2020);76:100889.

(4) Zhao N, Di B, Xu LL. The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies. Cytokine Growth Factor Rev. (2021);61:2-15.

(5) Zhao C, Zhao W. NLRP3 Inflammasome-A Key Player in Antiviral Responses. Front Immunol. (2020)18;11:211.

INFLAMMASOME SIGNALING PATHWAY BIOMARKER LIST

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at contact@anygenes.com to get started on your project.

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Signaling Pathways	Product ref	Informations
Inflammasome Signaling Pathway	IFS1H1	List infos

Species : Mus musculus (mouse)

Signaling Pathways	Product ref	Informations
Inflammasome Signaling Pathway	*******	List In progress...

Species : Rattus norvegicus (rat)

Signaling Pathways	Product ref	Informations
Inflammasome Signaling Pathway	*******	List In progress...

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
Inflammasome Signaling Pathway	*******	List In progress...

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