PRRs

Pattern Recognition Receptors (PRRs) recognize molecules from pathogens called PAMPs and molecules from damaged cells called DAMPs.

The four major sub-families of PRRs are Toll-like receptors (TLRs), NLRs, RLRs, and CLRs.

The Danger Theory, proposed by Polly Matzinger, suggests the immune system responds to tissue stress or damage via the release of DAMPs.

The three major types of molecularly controlled cell death involved in host defense are apoptosis, necroptosis, and pyroptosis.

Unlike necrosis, apoptosis is characterized by the preservation of plasma membrane integrity, which prevents the release of intracellular contents.

Morphological features of apoptosis include chromatin condensation, nuclear fragmentation, cell shrinkage, and the formation of apoptotic bodies.

Recognition of apoptotic cells by macrophages results in the production of anti-inflammatory molecules, specifically TGF-β and PGE2.

Apoptotic cells release "find-me" signals to recruit phagocytes, such as extracellular ATP and lysophosphatidylcholine (LPC).

In mammals, the inflammatory caspases (not related to apoptosis) include caspases 1, 4, 5, 11, 12, 13, and 14.

The executioner (effector) caspases in mammals are caspases 3, 6, and 7.

During apoptosis, phosphatidylserine (PS) residues are externalized from the inner to the outer leaflet of the plasma membrane.

In the intrinsic pathway of apoptosis, the apoptosome is formed by the association of cytochrome c, APAF-1, and pro-caspase-9.

The proteins SMAC/Diablo and HtrA2/Omi facilitate apoptosis by inhibiting IAPs (Inhibitors of Apoptosis Proteins).

In the extrinsic pathway, caspase-8 activation can be inhibited by c-FLIP, a catalytically-dead caspase-8 homolog.

Caspase-8 links the extrinsic pathway to the intrinsic pathway by cleaving BID into its active form.

TLR2 triggers apoptosis by recruiting the adaptor protein FADD via MyD88.

TLR3-induced apoptosis is mediated via the adaptor TRIF, which interacts with RIPK1 via its RHIM domain.

In human keratinocytes, poly I:C-induced apoptosis requires stimulation of TLR3 and its adaptor TRIF.

Necroptosis is a molecularly controlled form of cell death that exhibits a necrotic phenotype.

The first molecule identified in the necroptotic pathway was RIPK1, which is inhibited by necrostatin-1 (Nec-1).

RIPK1 recruits RIPK3 via their respective RHIM domains.

The executioner protein of necroptosis that translocates to the plasma membrane is MLKL.

MLKL induces membrane rupture by interacting with phosphatidylinositides in the plasma membrane.

The ESCRT-III machinery has been suggested to counter necroptosis by shedding damaged plasma membrane regions.

In the intrinsic pathway of apoptosis, cytochrome c associates with APAF-1 and pro-caspase-9 to form the apoptosome.

The extrinsic pathway of apoptosis can cross-talk with the intrinsic pathway via caspase-8 mediated processing of Bid.

In TNFR1 signaling, Complex IIb (the necrosome) forms when caspase-8 or FADD is absent/non-functional.

During TLR3- or TLR4-mediated necroptosis, RIPK1 is often dispensable and can even act as a negative regulator.

From a molecular standpoint, necroptosis is defined as a RIPK3-dependent form of cell death.

In TLR3-, TLR4-, and interferon-mediated necroptosis, RIPK1 is dispensable or even inhibitory to necrosome formation.

RIPK1 can inhibit necroptosis by recruiting FADD, which subsequently activates caspase-8 and FLIP.

Molecularly, necroptosis is strictly defined as a RIPK3-dependent form of cell death.

The plant-derived compound shikonin is unique because it can induce necroptosis even without the inhibition of FADD/caspase-8/FLIP.

Necroptosis is executed via plasma membrane permeabilization mediated by MLKL.

Deficiency in ESCRT-III results in faster necroptosis and reduced production of inflammatory cytokines.

Necroptotic cells are more immunogenic than apoptotic cells because they increase CD8+ T cell cross-priming.

The DAMP Calreticulin acts as an "eat me" signal and is primarily associated with apoptosis.

The DAMP HMGB1 signals through receptors such as RAGE and TLR2/4/9.

ATP acts as a DAMP by activating the NLRP3 inflammasome via P2X7 receptors.

Many human tumor samples evade immune attack by downregulating the expression of RIPK3 or MLKL.

Lower expression of RIPK3 or MLKL is associated with worse prognosis in breast and ovarian cancer, respectively.

Mice lacking RIPK3 are highly sensitive to vaccinia virus and Influenza A virus (IAV).

The pandemic 1918 and 2009 IAV strains suppress necroptosis via the hemagglutinin (HA) genomic segment.

The MCMV molecule vIRA contains a RHIM-like domain that blocks RIPK3 recruitment to RIPK1 and DAI.

In human cells, HSV-1 and HSV-2 suppress necroptosis using the proteins ICP-6 and ICP-10.

Necroptosis is detrimental in HIV infection because it eliminates HIV-specific CD8+ T cells.

In Influenza A (IAV) control, RIPK3 is essential, but MLKL is not, because RIPK3 also triggers apoptosis via FADD and caspase-8.

Pyroptosis is a necrotic form of regulated cell death that requires the inflammatory enzymes caspase-1 and/or caspase-11 (caspase-4/5 in humans).

The executioner of pyroptosis that forms pores in the plasma membrane is Gasdermin D (GSDMD).

Unlike apoptosis, DNA fragmentation in pyroptosis occurs independently of caspase-activated DNase (CAD).

Non-canonical inflammasome activation is initiated by the direct detection of cytosolic LPS by caspase-11 (or caspase-4/5).

The adaptor molecule that links many PRR sensors to pro-caspase-1 in the inflammasome is ASC.

The human orthologs of murine caspase-11 are caspase-4 and caspase-5.

The five major types of canonical inflammasomes are NLRP3, NLRP1, NLRC4 (NAIP), AIM2, and PYRIN.

Canonical inflammasome activation leads to the processing and release of the pro-inflammatory cytokines IL-1β and IL-18.

In the non-canonical inflammasome pathway, Lipid A (a component of LPS) binds directly to the CARD domain of pro-caspase-11.

LPS-induced lethal shock is primarily driven by the non-canonical inflammasome and the release of DAMPs like HMGB1 and IL-1α.

The effector protein of both canonical and non-canonical pyroptosis is Gasdermin D (GSDMD).

The N-terminal domain of GSDMD, known as the Pore-Forming Domain (PFD), oligomerizes in the plasma membrane to form pores of 10–33 nm.

The structure formed when bacteria remain trapped within pyroptotic cell corpses is called a pore-induced trap (PIT).

In neutrophils, GSDMD can be cleaved independently of caspases by neutrophil elastase (ELANE).

In neutrophils, the protease neutrophil elastase (ELANE) can cleave GSDMD independently of caspase activity.

The GSDMD pore is the molecular structure responsible for the non-conventional release of IL-1β and IL-18.

Why is LDH (lactate dehydrogenase) release considered an insufficient marker to distinguish viable from dying cells in inflammasome assays?

In mouse models of infection (e.g., L. monocytogenes), the deficiency of caspase-1/11 is generally more deleterious than the deficiency of IL-1β/IL-18.

In HIV patients, the depletion of quiescent CD4 T cells is primarily mediated by pyroptosis.

The PRR that senses cytosolic viral DNA in CD4 T cells to trigger HIV-induced pyroptosis is IFI16.

A hallmark of inflammasome activation found in the peripheral blood of HIV patients is the release of ASC specks.

What is the primary difference between immunogenic cell death (ICD) and non-immunogenic cell death regarding adaptive immunity?

Non-immunogenic apoptosis is characterized by the absence of plasma membrane leakage, which prevents the release of DAMPs.

In immunogenic cell death (ICD), the pre-apoptotic exposure of the ER-chaperone calreticulin promotes the uptake of dying cells by dendritic cells (DCs).

The early apoptotic secretion of ATP during ICD binds to P2X7 receptors on DCs, stimulating the formation of the NLRP3 inflammasome.

Passive release of the nuclear protein HMGB1 occurs during secondary necrosis and interacts with TLR4 on dendritic cells.

Anthracyclines can induce the release of RNA, which stimulates TLR3 to promote the secretion of the chemokine CXCL10.

Release of Annexin A1 after anthracycline treatment stimulates the Formyl Peptide Receptor 1 (FPR1) to direct DCs to dying tumor cells.

Defects in apoptotic cell clearance are linked to autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.

In necroptosis, immunogenicity is enhanced by the RIPK1-mediated activation of the NF-κB pathway.

Mitochondrial DAMPs, such as formyl peptides and mitochondrial DNA, act on FPR1 and TLR9 to induce neutrophil recruitment.

According to Table 2, the PRR for crystals and particulate matter is NLRP3, which induces pyroptosis.

According to Table 2, the intracellular sensor for dsDNA that induces pyroptosis is AIM2.

According to Table 2, the PRR for flagellin that specifically induces pyroptosis is NAIP/NLRC4.

Necroptosis is accompanied by the release of classical DAMPs, including HSPs, ATP, and HMGB1.

HMGB1 interacts with TLR3, 4, and 9 as well as RAGE to activate dendritic cells and macrophages.

Mitochondrial DAMPs such as formyl peptides and mitochondrial DNA act on FPR1 and TLR9 respectively.

The C-type lectin receptor Mincle (CLEC4E) interacts with the necrotic DAMP SAP130.

Released uric acid can precipitate into monosodium urate (MSU) crystals, which activate the NLRP3 inflammasome.

During necrosis, dsDNA stimulates the AIM2 inflammasome and the RLR family members RIG-I and MDA5.

Unlike other cytokines, full-length IL-33 acts as a DAMP during necrosis because it retains immunological activity in the absence of caspase processing.

Necroptosis and pyroptosis are considered necrotic forms of cell death and are associated with a pro-inflammatory outcome.

The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis.

The pseudokinase MLKL is a key downstream component of RIP3 that mediates necroptosis.

Necroptosis is executed when MLKL translocates to the plasma membrane and compromises its integrity.

Proapoptotic signaling through TLR3 involves TRIF-dependent activation of caspase-8.

The formation of the Ripoptosome (a RIP1/caspase-8 complex) is blocked by cIAPs.

Phosphatidylserine externalization during CD95 (Fas)-induced apoptosis requires caspase (ICE/CED-3) activity.

Necroptosis requires the translocation of trimerized MLKL protein to the plasma membrane.

MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates.

Upon phosphorylation by RIP3, MLKL forms cation channels that disrupt the cell membrane.

ESCRT-III acts downstream of MLKL to regulate and potentially delay necroptotic cell death.

Virus-induced programmed necrosis can be mediated by the complexing of DAI (ZBP1) with RIP3.

The induction of necroptosis via viral activation can occur through the RIG-I or STING pathways.

The Ripoptosome is a signaling platform that assembles in response to genotoxic stress and loss of IAPs.

Immunogenic cancer cell death is characterized by the exposure of calreticulin and the secretion of ATP.

Necrotic cells trigger a sterile inflammatory response primarily through the NLRP3 inflammasome.

The adaptor ASC has 'prionoid' activities that allow it to propagate inflammation extracellularly.

Cyclophilin A is a damage-associated molecular pattern (DAMP) that mediates acetaminophen-induced liver injury.

Unlike apoptosis, necrotic cell death releases heat shock proteins (HSPs), which activate the NF-κB pathway in dendritic cells.

The extracellular release of HMGB1 occurs during both necrosis and late stages of apoptosis.

Chemotherapy and radiotherapy rely on the immune system via a Toll-like receptor 4 (TLR4)-dependent mechanism.

The alarmin HMGB1 is released into the extracellular space during apoptotic cell death.

In acute lung injury, alveolar macrophage pyroptosis is mediated by the NLRP3/ASC complex, leading to HMGB1 secretion.

The cytokine IL-1α is biologically active as a precursor and serves as a key alarmin in the IL-1 family.

Interleukin-33 (IL-33) signals through the ST2 receptor and typically induces T helper type 2 (Th2) cytokines.

Unlike apoptosis, necrosis is specifically associated with the production of the pro-inflammatory cytokine IL-6.

Mitochondrial DNA (mtDNA) can activate the NLRP3 inflammasome and is linked to the development of Type 1 diabetes.

The receptor Mincle is an ITAM-coupled activating receptor that senses damaged cells.

Soluble uric acid acts as a DAMP that promotes inflammation by activating the NLRP3 inflammasome.

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

In the absence of MLKL, RIPK3 can still promote cell death and NLRP3 inflammasome activation.

In the absence of MLKL, RIPK3 can still promote cell death and NLRP3 inflammasome activation.

Vaccination with necroptotic cancer cells has been shown to induce efficient anti-tumor immunity.

Methylation-dependent loss of RIP3 (RIPK3) expression in cancer cells leads to repression of programmed necrosis (necroptosis) in response to chemotherapy.

Low expression of Mixed Lineage Kinase Domain-like protein (MLKL) is associated with a poor prognosis in ovarian cancer patients.

The Herpes Simplex Virus 1 (HSV-1) protein ICP6 triggers host antiviral defense by directly activating the RIP3/MLKL necroptosis pathway in mice.

Caspase-8 and FADD are essential for preventing necroptosis during embryonic development, as their absence leads to prenatal lethality.

Pyroptosis is a form of cell death characterized by Caspase-1-dependent pore formation and subsequent osmotic lysis.

Non-canonical inflammasome activation is triggered by intracellular (cytoplasmic) LPS, which directly activates Caspase-11 (in mice) or Caspase-4/5 (in humans).

The executioner of pyroptosis is Gasdermin D (GSDMD), which is cleaved by inflammatory caspases to form membrane pores.

Non-canonical inflammasome signaling involves Caspase-11 (in mice) or Caspase-4/5 (in humans) cleaving Gasdermin D (GSDMD) to induce pyroptosis.

The executor of pyroptosis, Gasdermin D (GSDMD), is required for the secretion of the pro-inflammatory cytokine IL-1β.

Chemotherapy drugs can induce pyroptosis through Caspase-3 cleavage of Gasdermin E (DFNA5).

Pyroptosis triggers the formation of pore-induced intracellular traps (PITs), which capture bacteria for clearance by efferocytosis.

In neutrophils, the NLRC4 inflammasome can promote IL-1β maturation without necessarily inducing pyroptosis.

The IFI16 DNA sensor is required for the death of lymphoid CD4 T cells abortively infected with HIV.

In human monocytes, an alternative inflammasome pathway allows for IL-1β secretion without the immediate induction of pyroptotic cell lysis.

The innate immune response against Francisella tularensis is dependent on the ASC/caspase-1 axis.

In HIV-1 infection, the IFI16 DNA sensor is required for the death of lymphoid CD4 T cells that are abortively infected.

CD4 T-cell depletion in HIV-1 infection is primarily driven by cell death via pyroptosis.

The suppression of interleukin-33 (IL-33) bioactivity occurs through proteolysis by apoptotic caspases.

Anticancer chemotherapy-induced antitumor immunity requires the formyl peptide receptor 1 (FPR1).

Innate immune recognition of infected apoptotic cells directs the differentiation of TH17 cells.

The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo.

Gout-associated uric acid crystals activate the NALP3 (NLRP3) inflammasome.

Toll-like receptor 3 (TLR3) can mediate necrosis via a pathway involving TRIF, RIP3, and MLKL.

Agonistic targeting of TLR1/TLR2 induces apoptosis in AML cells via a p38 MAPK-dependent mechanism.

Toll-like receptor 3 (TLR3) can induce programmed necrosis (necroptosis) via a signaling complex involving TRIF, RIP3, and MLKL.

The NLRP3 inflammasome is activated by non-microbial sterile signals such as silica crystals, aluminum salts, and asbestos.

In the context of cardiovascular disease, cholesterol crystals are known to activate the NLRP3 inflammasome, contributing to atherogenesis.

The NLRC4 inflammasome specifically recognizes bacterial flagellin and components of the Type III Secretion System (T3SS).

Cytosolic double-stranded DNA (dsDNA) is recognized by the AIM2 inflammasome, which then recruits ASC to activate caspase-1.

The Pyrin inflammasome senses bacterial modifications (such as inactivation) of host Rho GTPases.

Extracellular ATP triggers the P2X7 receptor to induce K+ efflux, a common secondary signal for NLRP3 activation.

The DNA sensor DAI (ZBP1) can sense influenza A virus genomic RNA to activate RIPK3-dependent cell death.