AUTHOR=Dai Ting , Zhao Ziyue , Zhu Tingfang , Fei Chenjie , Nie Li , Chen Jiong 

TITLE=The anti-inflammatory role of zDHHC23 through the promotion of macrophage M2 polarization and macrophage necroptosis in large yellow croaker (Larimichthys crocea)

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1401626

DOI=10.3389/fimmu.2024.1401626

ISSN=1664-3224

ABSTRACT=<p>Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (<italic>Larimichthys crocea</italic>), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 <italic>Lc</italic>zDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all <italic>Lc</italic>zDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, <italic>Lc</italic>zDHHC23 exhibited the most pronounced upregulation following <italic>Pseudomonas plecoglossicida</italic> (<italic>P. plecoglossicida</italic>) infection of macrophage/monocyte cells (MO/MΦ). Silencing <italic>Lc</italic>zDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, <italic>Lc</italic>zDHHC23 facilitated M2-type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon <italic>Lc</italic>zDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by <italic>P. plecoglossicida</italic> infection. These findings highlight the non-PAT immunomodulatory function of <italic>Lc</italic>zDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting <italic>Lc</italic>zDHHC23 as a potential therapeutic target for immune modulation in aquatic species.</p>