Samali - inflammasome, TLRs and NLRs PDF

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inflammasome, TLRs and NLRs Innate immune function depends upon recognition of the pathogen associated molecular patterns (PAMPs) and derived from invading pathogens (DAMPs), induced as a result of endogenous stress by germline-encoded pattern recognition receptors (PPRs). Activation of PPRs by PAMP...

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inflammasome, TLRs and NLRs Innate immune function depends upon recognition of the pathogen associated molecular patterns (PAMPs) and derived from invading pathogens (DAMPs), induced as a result of endogenous stress by germline-encoded pattern recognition receptors (PPRs). Activation of PPRs by PAMPs or DAMPs triggers downstream signalling cascades and leads to the production of type 1 interferon proinflammatory cytokines, immune cell recruitment and inflammation. There are 4 major classes of PPRs. toll like receptors (TLRs) are single, membrane spanning, non-catalytic receptors usually expressed on macrophages and dentric cells that recognise structurally conserved molecules derived from bacteria, viruses and parasites. Once these microbes preach physical barriers e.g. skin, they are recognised by TLRs which activate immune cell responses. TLRs recognise PAMPs and DAMPs. PAMPs include various bacterial cell wall components such as LPS, peptidoglycan (PGN) and lipopeptides as well as flagellin, bacterial DNA and viral dsDNA. DAMPs include intracellular proteins such as HSPs as well as protein fragments from the extracellular matrix. Stimulation of TLRs via PAMPs or DAMPs initiates signalling cascades leading to the activation of transcription factors such as AP-1, NF-kB and interferon regulatory factors (IRFs). Signalling through TLRs result in the production of interferons (IFNs), proinflammatory cytokines and effector cytokines that direct the adaptive immune response. TLR activation by LPS result in a proinflammatory reSponse through NF-kB. TLR4 is specifically activated by LPS molecules which are found in the outer membrane of gram bacteria. They are composed of a lipid and a saccaride component and are highly immunogenic, they can often cause septic shock and lead to cell death. Upon binding of a ligand MyD88 binds its TIR domain and assembly of IRAK1/4 complex begins. IRAK4 phosphorylates 1, creating a binding site for TRAF6. The IRAK1-TRAF6 complex dissociates and activates the protein kinase TAK1 complex. Active TAK1 may activate either the NFKB pathway of the MAP kinase pathway leading to either NF-KB or MAPK dependent transcription and activation of downstream effector molecules.

Activation of the inflammasome is a key function mediated by the innate immune system. Several families of the PPR are important components of the inflammasome complex, including NOD-like receptors (NLRs) and absent in melanoma-like receptors (ALRs; AIM-2 like receptors). The NLR family of PPRs has 23 members. They cytosolic and work synergistically with TLRs. inflammasomes are multimeric protein complexes that assemble in the cytosol after sensing PAMPs or DAMPs. In general inflammasomes serve as a scaffold to recruit the inactive zymogen pro-caspase-1. The relevant NLR or AIM2 can olgiomerize rendering active caspase-1. The active caspase-1 is a cyesteine-dependent protease which cleaves and activates IL1-B and IL-18. This leads to the amplification of the inflammatory system and to cell death via pyroptosis. Most inflammasomes are formed with one or two NLR family members e.g. NLRP1, NLRP3, NLRC4. NLRC4 requires interaction with an NLR member of the NAIP superfamily of proteins. non-NLR proteins such as AIM2 and pyrin can also form inflammasomes. NLRC4 can directly associated with caspase-1 through CARD-CARD interactions. NLRs containing an amino-terminal pyrin domain (PYD) are shown to associated with apoptosis associatedspeck-like protein containing a CARD (ASC) in order to recruit pro-caspase-1 to the inflammasome. NLRP3 inflammasome The NLRP3 inflammasome is activated in response to the widest array of stimuli and it is believed that dissimilar agonists induced similar downstream events which are senses by NLRP3. The mechanisms of NLRP3 activation, which are supported by most studies, include potassium efflux out of the cell, the generation of mitochondrial ROS, translocation of the NLRP3 to the mitochondria, the release of mitochondrial DNA, or the release of cathepsins into the cytosol after lysosomal destabilisation. Not all of these events are induced by NLRP3 agonists, so the mechanism of it activation is still debated. Additionally increasing concentrations of calcium can activate NLRP3 inflammasome. In most cell types, NLRP3 must be primed. An example of such priming is the binding of LPS to TLR4. Priming is known to increase the cellular expression of NLRP3 through NF-kB signalling. Once primed, NLRP3 can respond to its stimulus and assemble the inflammasome. Additionally, ASC must be linearly ubiquitinated for NLRP3 inflammsome assembly. Current stimuli recognised as NLRP3 agonists that induce NLRP3 inflammasome formation include ATP, pore forming toxins, crystalline susbtances, nucleic acids, hyaluronan, and fungal, bacterial and viral pathogens. These stimuli can be encountered

during infection, either produced by pathogens or released by damaged host cells. Studies identified that the NLRP3 NBD oligomerises the NLRP3 PYD, which serves as a scaffold to nucleate ASC proteins through PYD-PYD interactions. This causes ASC to generate long ASC filaments that are crucial to inflammasome activation. Pro-caspase-1 then interacts with ASC through CARD-CARD interactions - caspase-1 activated.

Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. Caspase-1 is activated within multi‐ protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Caspase‐ 1 process GSDMD, which results in release of the GSDMDNterm fragment. GSDMDNterm forms a large pore in the plasma membrane. Pore formation results in rapid loss of membrane integrity, the dissipation of the electrochemical gradient, and ultimately in cell death.

The inflammasome and Alzheimer's disease (AD). Accumulation of amyloid-β plaques in the cerebrum is a characteristic of AD. Amyloid-β peptide is regularly formed in cerebral tissue by cleavage of the amyloid precursor protein, but it can form prion-like misfolded oligomers in the case of AD74. Amyloid-β was the first molecule associated with neurodegenerative disease models that was found to activate the mouse NLRP3 inflammasome, resulting in IL-1β production75. Fibrillary amyloid-β induces NLRP3 inflammasome–dependent activation of caspase-1 through a mechanism dependent on endosomal rupture and cathepsin B release in LPS-primed mouse macrophages.

The innate immune system depends on the recognition of DAMP and PAMps which are a result of endogenous stress, by pattern recgontition recptors PPRs. the activation of the inflammasome is a key process of the immune respones. Several ppr are imporatnt

componenets of the inflammasomes including NLR and ALRs. it is activated in the cytosol by recognises PAMPs and DAMPs. In general it acts as a scaffold for the recruitment of the inactive zymogen pro caspase I. oligomerization of the relevenat NLR or ALR can renders the caspsase I aactive. It the acitvae il1 b il18 amplifying the immune response and leading to cell death by pyroptosis. The inflammasome is usally composed of one or two NLRS NLRP1 NLRP3 NLRC4. NLRC4 can interact with capase I directly through card card domains. NLRP3 must be primed. An example of this priming it the binding of LPS to TLR4. this priming increases the expression of NLRP3. Once primeed nlrp3 can reocngonsie stimuli and be activated. Stimuli include nuleais acid tocins atp and bacterla and virla pathogene. th...