Inflammasomes in Teleosts: Structures and Mechanisms That Induce Pyroptosis during Bacterial Infection

Abstract

Pattern recognition receptors (PRRs) play a crucial role in inducing inflammatory responses; they recognize pathogen-associated molecular patterns, damage-associated molecular patterns, and environmental factors. Nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptors (NLRs) are part of the PRR family; they form a large multiple-protein complex called the inflammasome in the cytosol. In mammals, the inflammasome consists of an NLR, used as a sensor molecule, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as an adaptor protein, and pro-caspase1 (Casp1). Inflammasome activation induces Casp1 activation, promoting the maturation of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and the induction of inflammatory cell death called pyroptosis via gasdermin D cleavage in mammals. Inflammasome activation and pyroptosis in mammals play important roles in protecting the host from pathogen infection. Recently, numerous inflammasome-related genes in teleosts have been identified, and their conservation and/or differentiation between their expression in mammals and teleosts have also been elucidated. In this review, we summarize the current knowledge of the molecular structure and machinery of the inflammasomes and the ASC-spec to induce pyroptosis; moreover, we explore the protective role of the inflammasome against pathogenic infection in teleosts.

Keywords: ASC; Caspase-1; NLR; gasdermin; inflammasome; pattern recognition; pyroptosis.

Figure 1

Phylogenetic relationship of the nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptor family in mammals (human and mouse) and fish (Japanese medaka and zebrafish). The tree was constructed using the MEGAX and a neighbor-joining method with 1000 bootstrap replications. The black triangle shapes show collection of the clusters.

Figure 2

Differences between the cyprinids and other fish species in their inflammasome activation and pyroptosis pathways. In the most fish, the nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptor (NLR) family recognizes the ligands, and bind to apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-Caspase1 (Casp1) via pyrin domain (PYD)-PYD and caspase recruitment domain (CARD)-CARD interactions, thus forming the inflammasome. However, in cyprinids, ligands recognize the NLR family and construct two types of inflammasomes: in the first, the NLR family binds to ASC and pro-CaspA/B via CARD–CARD and PYD–PYD interactions, respectively. The NLR family interacts with ASC via the PYD–PYD interaction, and the ASC oligomerization occurs via CARD–CARD (called ASC core). Then, the pro-CaspA/B binds to the ASC core via the PYD–PYD interaction. After activation, the Casp1/A/B undergoes self-proteolysis, and the Casp1 matures interleukin-1β, inducing pyroptosis through gasdermin-E cleavage in all fish, including cyprinids. In addition, the cyprinid’s CaspB works as a non-canonical inflammasome activator, similar to mammalian Casp4/5/11. The pro-CaspB directly recognizes liposaccharides and thus activates by itself.