INTRODUCTION
Bacteria, fungi, viruses, and protozoa are capable of causing infection, potentially leading to death of the host. The host immune system acts as a guardian and defends the body from challenge by pathogens. Both innate and adaptive immune systems contribute to the killing and clearance of invading microbes.
Pattern recognition receptors (PRRs) of the innate immune system initiate sensing of pathogens and danger signals by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), respectively. Activation of PRRs induces a cascade of inflammatory host responses that, in most cases, rapidly resolve the infection (1).
However, inflammation is a double-edged sword and can result in the development of autoimmunity, inflammatory diseases, and cancer. PRRs evoke diverse antimicrobial activities by initiating activation of the transcription factor NF- κB, mitogen-activated protein kinase (MAPK), and interferon (IFN) signaling pathways, leading to the transcription of hundreds of genes that collectively induce an antipathogen state in the cell.
PRRs include the family members Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), AIM2-like receptors (ALRs), and cytoplasmic DNA and RNA sensors (2–4).
Both membrane-bound and cytoplasmic sensors function synergistically to mount an effective antimicrobial response against invading microbes. TLRs and CLRs are membrane-bound receptors which detect PAMPs and DAMPs on the cell surface and within endosomes.
Membrane bound organelles include:
- The nucleus
- Endoplasmic reticulum
- Golgi apparatus
- Vacuoles
- Lysosomes
- Mitochondira
- and in plants, chloroplasts
ALRs, NLRs, RLRs, and cytoplasmic DNA and RNA sensors recognize PAMPs and DAMPs that have reached the cytoplasm of the cell, which is achieved via either infection by pathogens or damage to organelles of the host cell leading to the release of endogenous DAMPs. Certain NLRs and ALRs assemble inflammasome complexes in response to PAMPs and DAMPs (5).
The inflammasome is a multiprotein complex which regulates activation of the cysteine protease caspase-1, leading to proteolytic processing and secretion of the proinflammatory cytokines interleukin-1 (IL-1) and IL-18. In addition, this multimeric complex induces an inflammatory form of cell death called pyroptosis (6). An inflammasome complex comprises one or more sensors (NLRs, ALRs, or Pyrin), the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 (7, 8) (Fig. 1A).
FIG 1 Architecture of inflammasome complexes. (A) Formation of an inflammasome complex is initiated by an inflammasome sensor. Inflammasome sensors carry a pyrin domain (PYD) and/or a caspase activation and recruitment domain (CARD). They may also carry a leucine-rich-repeat domain (LRR), a nucleotide-binding domain (NBD), a HIN-200 domain, a B30.2 domain, a coiled-coil domain (C-C), a B-box domain (B), a function-to-find domain (FIIND), or a baculovirus inhibitor of apoptosis repeat (BIR). Other inflammasome components include the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the effector protein caspase-1. A PYD-containing inflammasome sensor interacts with the PYD of ASC, allowing the CARD of ASC to interact with the CARD of caspase-1. A CARD-containing inflammasome sensor can interact with the CARD of ASC, whereby the PYD of ASC interacts with the PYD of an additional ASC. The CARD of ASC then interacts with the CARD of caspase-1. Alternatively, a CARD-containing inflammasome sensor may directly interact with caspase-1 via their respective CARDs.
(B) Canonical inflammasome complexes are activated by a range of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Caspase-1 cleaves the pore-forming factor gasdermin D, whereby the N-terminal domain of gasdermin D forms pores in the host cell membrane. Caspase-1 also cleaves the proinflammatory cytokines pro-IL-1 and pro-IL-18, generating biologically active versions of these cytokines for release through the membrane pores generated by gasdermin D. The pores formed by gasdermin D also lead to lytic cell death via pyroptosis.
(C) The noncanonical inflammasome is a pathway specifically activated by Gram-negative bacteria. In this pathway, lipopolysaccharides (LPS) are introduced into the cytoplasm during infection and sensed by human caspase-4 and caspase-5 and mouse caspase-11. These inflammatory caspases can also cleave gasdermin D, in a manner similar to that by caspase-1, leading to the induction of pyroptosis. The N-terminal domain of gasdermin D also induces activation of the NLRP3 inflammasome and the associated proteolytic cleavage of pro-IL-1 and pro-IL-18.
On stimulation with PAMPs or DAMPs, an inflammasome sensor is activated and associates with ASC, thereby leading to oligomerization of ASC and formation of a filamentous scaffold (9, 10).
ASC filaments interact with inactive procaspase-1 monomers to facilitate proximityinduced activation of caspase-1 (9, 10). This sensor–ASC– caspase-1 scaffold can readily be visualized endogenously as a cytoplasmic speck of 0.8 to 1 m in diameter (11–14). Furthermore, inflammasome specks act as DAMPs following their release by pyroptotic cells, resulting in amplification of inflammation (15, 16). Caspase-1 activated within the inflammasome complex executes pyroptosis by inducing cleavage of the propyroptotic factor gasdermin D (17–19), yielding a cleaved N-terminal fragment of gasdermin D that oligomerizes and forms pores on the host cell membrane (20–24) (Fig. 1B).
The consequences of this event are cell swelling, lytic cell death, and liberation of cytoplasmic contents, including biologically active IL-1 and IL-18. Evidence suggests that the pores formed by gasdermin D allow passive release of IL-1 and DAMPs of less than 10 to 16 nm in diameter from the cytoplasm of macrophages to the extracellular space, even prior to lysis and death of the host cell (25–27). Self-cleavage of caspase-1 at the caspase activation and recruitment domain (CARD) linker region releases caspase-1 from the inflammasome complex, resulting in termination of caspase-1 activity (28). Pathogens have evolved various immune evasion mechanisms. To counteract these evasion strategies, both extracellular and intracellular surveillance systems must overlap and operate in unity to provide efficient recognition of the pathogen. This review focuses on the diverse cytosolic innate immune recognition pathways of microorganisms, with a focus on inflammasome sensors and the respective families of PAMPs that they recognize. We also shed light on the downstream effector functions of the inflammasome that drive protection against infectious diseases.