INNATE IMMUNE SYSTEM ACTIVATION

Next, I would like to explain how the innate immune system senses microbes invading our body.

As I told you a while ago, innate immune cells have sensors that detect pathogens, which are

collectively called innate immunity receptors.

These receptors are activated by mainly two types of molecular patterns.

One of them is called pathogen-associated molecular patterns or PAMPs, which are structures

produced by microorganisms but not mammalian cells.

Typical examples are microbial DNAs, RNAs, and cell wall components such as bacterial

lipopolysaccharides.

The other is called damage or danger-associated molecular patterns.

They are endogenous molecules produced by or released from damaged or dying cells.

Examples include high-mobility group box1 (HMGB1) proteins, S100 proteins, uric acid crystals,

and purine metabolites such as extracellular ATP (Adenosine Triphosphate).

Because the innate immunity receptors recognize these structures conserved or shared among

pathogens or damaged cells, they are often called pattern recognition receptors.

So, sensors of the innate system are pattern recognition receptors.

And, these pattern-recognition receptors are expressed ubiquitously.

They include cell surface-associated Toll-like receptors (TLRs) and lectin receptors that

recognize microbial cell surface components, cytoplasmic NOD-like receptors and RIG-like

receptors, and endosome-associated Toll-like receptors that recognize nucleic acids of ingested

microbes.

So, innate immunity receptors are expressed ubiquitously.

Among the pattern recognition receptors, Toll-like receptors or TLRs have been the most studied

so far.

There are at least nine different Toll-like receptors, depending on their localization, and Toll-like

receptors respond to various PAMPs and DAMPs.

For instance, Toll-like receptor-1, -2, -4, -5, and -6 recognize microbial cell wall components,

whereas Toll-like receptor-3, -7, -8, and -9, which are all expressed on the endosomal

membrane, recognize nucleic acids.

These Toll-like receptors all contain a ligand-binding domain composed of leucine-rich motifs

and a cytoplasmic signaling domain or TIR domain.

When microbial components bind to Toll-like receptors via the Toll-like receptor's leucine-rich like

domain, the signals are transmitted intracellularly via the TIR domain, and as a result, various

adaptor proteins are recruited locally, and cytoplasmic transcription factors including NF-κB and

interferon-regulatory factors or IRFs are subsequently activated.

IRF activation induces production of type-1 interferons such as interferon alpha and beta, thus

inducing anti-viral states in the cell.

NF-κB activation induces expression of certain proinflammatory cytokines and adhesion

molecules, both of which help promote acute inflammation.

NF-κB activation also induces expression of costimulatory molecules that are required for

induction of adaptive immunity.

I will tell you more about costimulatory molecules later in this talk.

Among the innate immune receptors, NOD-like receptors or NLRs sense PAMPs and DAMPs in

the cytoplasm.

When NLRs are engaged, it stimulates the formation of the inflammasome complex, which

is a multiprotein complex that mediates activation of caspase-1, and activated caspase-1

proteolytically generates the active form of interleukin-1 or IL-1 from an inactive precursor.

IL-1 is one of the strongest cytokines that can induce inflammation.

So, because IL-1 is, so called, a typical proinflammatory cytokine, this process helps promote

inflammatory responses.

In this slide, one of the NLRs, NLRP-3, is activated by PAMPs or DAMPs, and forms oligomers

with an adaptor protein and an inactive form of caspase-1, which leads to activation of

caspase-1, which in turn activates IL-1.

IL-1 is constitutively produced in inflamed cells as inactive form.

But activated caspase-1 activates IL-1 to induce acute inflammation.

And Toll-like receptor signaling also enhances this process.

So, upon sensing of PAMPs and DAMPs, NLRP-3 oligomerizes with an adaptor protein and

inactive form of caspase-1.

Once recruited, caspase-1 is activated, and cleaves pro-IL-1 (inactive from of IL-1), to generate

biologically active IL-1.

And IL-1 induces acute inflammation and causes fever.

And among these proinflammatory cytokines, you have IL-1, IL-18, TNF (tumor necrosis factor),

and Interleukin-6 and so on.

share this article to: Facebook Twitter Google+ Linkedin Technorati Digg

Posted by Unknown, Published at 12:31 م and have 0 التعليقات