Pattern Recognition Receptors and Their Role in Cell Death

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Instigating cell death during pathogen invasion

Pattern recognition receptors (PRRs) are involved in the protection against invading pathogens, and activated either by recognizing conserved pathogen associated molecular patterns (PAMPs), unique to each pathogen, or damage associated molecular patterns (DAMPs), which signal cells are in stress or have been damaged. Read our overview on PRR to learn more about these receptors that identify and respond to infection.

Once PAMPs and/or DAMPs have been recognized, PRR engage with immune cells and the resultant signals generate pro-inflammatory and microbiocidal responses resulting in the death of an infected cell. Pattern recognition receptors are involved in instigating three mechanisms of regulated cell death.


Apoptosis

PRR induced apoptosis occurs less frequently than the other PRR instigated mechanisms of cell death. Here Toll-like receptors (TLR), a subfamily of PRRs, trigger apoptosis in three main ways.

TLR Pathway

Activation

TLR2 Pathway

Recruitment of Fas-associated protein with death domain (FADD) via myeloid differentiation primary response gene 88 (MyD88), leading to activation of caspase-8 and apoptosis.

TLR3 Pathway

Mediated by Toll/IL-1 receptor domain-containing adaptor inducing interferon (IFN)-β (TRIF) interaction with receptor-interacting serine/threonine-protein kinase 1 (RIPK1), resulting in FADD recruitment that activates caspase-8 and in turn apoptosis.

TLR4 Pathway

Apoptosis activation mediated either by TRIF or MyD88.


Necroptosis

Cells that are undergoing necroptosis are highly immunogenic and potent inducers of an inflammatory response, critical in an effective response to infection. Necroptosis is activated by different PRR subfamilies including:

  • Toll-like receptors - TLR3 (recognizes viral RNA) and TLR4 (recognizes bacterial lipids)
  • Retinoic acid-inducible gene I (RIG-I) like receptors (RLR) - RIG-I and melanoma differentiation-associated gene 5 (MDA5) that recognize viral RNA

Activation of necroptosis is a RIPK1 independent process and relies upon RIPK3 recruitment. This results in the release of intracellular content including DAMPs by mixed lineage kinase domain-like (MLKL) mediated plasma membrane permeabilization.


Pyroptosis

This type of cell death can be initiated by the interaction of PRRs which can facilitate the formation of an inflammasome. There are two types of inflammasomes:

  1. Non-canonical inflammasomes , composed of caspase-11, functioning as both sensor and death instigator, and seemingly not involving PRRs.
  2. Canonical inflammasomes, composed of PRR derived sensor proteins. There are 5 main types of PRR sensors: NLR pyrin domain containing 3 (NLRP3); NLRP1; neuronal apoptosis inhibitory protein (NAIP)/NLRcard-containing 4 (NLRC4); absent in melanoma 2 (AIM2); and pyrin. Activation of any of these cytosolic sensors in response to PAMPs and DAMPs can lead to the recruitment of caspase-1 and ultimately cell death via pyroptosis.

The resultant actions of these forms of cell death lead to the release of DAMPs, which in turn stimulate PRR, thereby providing a positive feedback loop that amplifies the host defence mechanism against pathogens.


PRR Cell Death Sensing

Upon recognition of DAMPs, PRR go on to alert and induce the immune system to increase phagocytosis and the production of pro-inflammatory cytokines, but also to induce cell death. The type of cell death stimuli influences the type of DAMP released, which in turn is recognized by different PRRs, leading to the initiation of different cell death mechanisms. Table 1 lists different DAMPs, the PRRs that recognize them, the associated cell death mechanism  initiated, plus associated product links to the PRRs.

Table 1. DAMPs, PRRs, and the cell death mechanism.

DAMPs

PRRs

Cell Death Mechanism

Pam3CysK

Lipoproteins

TLR2

Necroptosis

Apoptosis

Poly(I:C)

TLR3

Necroptosis

Apoptosis

LPS

HMGB1

TLR4

Necroptosis

Apoptosis

Bacterial RNA

ATP

Bacterial pore-forming toxins

dsRNA

NLRP3

Pyroptosis

Toxin-modified RHO GTPase

Pyrin

Pyroptosis

ssRNA

shRNA

RIG-I

Necroptosis

Apoptosis

Flagellin

NAIP/NLRC4

Pyroptosis

Table adapted from Amarante-Mendes GP et al. 2018.

Read our overview on PRR to learn more about these receptors that identify and respond to infection, and see which antibodies are available to identify these critical immune receptors.


Reference

  • Amarante-Mendes GP et al. (2018). Pattern recognition receptors and host cell death molecular machinery. Frontiers in Immunology 9; 1-19.