Fish Shellfish Immunol 2025 Apr 14;162:110340. doi: 10.1016/j.fsi.2025.110340.

A novel double Ig interleukin-1 receptor-related molecule from Apostichopus japonicus alleviates Vibrio splendidus-induced inflammation.

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In vertebrates, the single immunoglobulin (Ig) interleukin-1 receptor-related molecule, SIGIRR, plays a role in controlling inflammatory responses. Its invertebrate homologous double Ig interleukin-1 receptor-related molecule, DIGIRR, is little known. We report here the cloning of a novel DIGIRR homologue in Apostichopus japonicus, named AjDIGIRR, using rapid amplification of cDNA ends (RACE). Gene structure analysis revealed that AjDIGIRR contains a conserved intracellular TIR domain that differs from SIGIRR and IL-1R by having a different number of extracellular Ig domains. Subcellular localization analysis showed that, unlike fish DIGIRR, which is cytoplasmic, AjDIGIRR was membrane-associated and had increased expression 24 h after infection. In vertebrates, two amino acid sites in the TIR domains of IL-1R family members, Ser and Arg-Tyr, are conserved and are required for receptor signaling. Sequence alignment revealed that the primary signaling site, S279, is conserved in DIGIRR, whereas the signal activation site, Arg-Tyr536, is mutated to Gln-Gly359 in AjDIGIRR. To investigate AjDIGIRR's role in inflammation regulation, an in vivo inflammation model was established using Vibrio splendidus. Following bacterial challenge, AjDIGIRR mRNA expression in coelomocytes peaked at 6 h (1.92-fold increase) and remained elevated (1.63-fold increase) for up to 48 h, consistent with the inflammatory response. AjDIGIRR knockdown (0.26-fold) significantly exacerbated inflammation, as shown by HE staining, whereas overexpression (7.85-fold) markedly alleviated the inflammatory response. Under inflammatory conditions, AjDIGIRR overexpression reduced IL-17 expression by 29 % compared to the V. splendidus-induced group. These findings suggest that AjDIGIRR is structurally and functionally more similar to mammalian SIGIRR than to fish DIGIRR. Acting as a key negative regulator, AjDIGIRR mitigates inflammation by downregulating IL-17 expression.

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