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inflammasome

Friday 11 January 2008

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Definition : The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses.

The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines Interleukin 1β (IL-1β) and Interleukin 18 (IL-18).

The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis.

n the case of dysregulation of the inflammasome, an assortment of major diseases may arise.

It is expressed in myeloid cells and is a component of the innate immune system.

The inflammasome complex can consist of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3).

NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) and ALRs (AIM2-like receptors) can also form an inflammasome.

The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, e.g. dsRNA will trigger one inflammasome composition whereas asbestos will assemble a different variant.

Because the pro-inflammatory pathway does not need Toll-like receptors (TLRs), inflammasomes with AIM2 can detect cytoplasmic DNA, a danger signal, that may be threatening and strengthen their innate response.

Pattern-recognition receptors, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), are able through the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns to sense microbe-dependent and microbe-independent danger and thereby initiate innate immune responses.

The innate immune system provides the host with an immediate and rapid defense against invading microbes. Detection of foreign invaders is mediated by a class of receptors that are known as the pattern recognition receptors, such as the family of Toll-like receptors (TLRs).

NALPs

NALPs are implicated in the activation of proinflammatory caspases (CASP1) (MIM.147678) via their involvement in multiprotein complexes called inflammasomes.

Toll-like receptors (TLRs)

In humans, ten functional TLRs have been identified and they respond to conserved pathogen-associated molecular patterns derived from bacteria, mycoplasma, fungi and viruses. TLR activation leads to direct antimicrobial activity against both intracellular and extracellular bacteria, and induces an antiviral gene program.

TLR2 activation leads to the use of vitamin D3 as a mechanism to combat Mycobacterium tuberculosis.

Pathology

In some autoinflammatory conditions, abnormalities in NLR signaling pathways and NLRs are involved in pathogenesis, as exemplified by NOD2 mutations associated with Crohn’s disease. Some other NLRs are components of the inflammasome, a caspase-1- and prointerleukin-1beta-activating complex.

The inflammasome has a central role in innate immunity. Some monogenic hereditary inflammatory diseases, such as Muckle-Wells syndrome, are associated with mutations in proteins that modulate the activity of the inflammasome, and on some multifactorial disorders, such as Type 2 diabetes and hypertension.

See also

- innate immune responses
- innate immune system
- innate immunity
- TLR recptors (TLRs)
- non-TLR receptors

References

- Faustin B, Reed JC. Sunburned skin activates inflammasomes. Trends Cell Biol. 2008 Jan;18(1):4-8. Epub 2007 Dec 20. PMID: 18083030

- McDermott MF, Tschopp J. From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. Trends Mol Med. 2007 Sep;13(9):381-8. PMID: 17822957