Abstract
R848 is an imidazoquinoline compound that is a specific activator of toll-like receptor (TLR) 7/8 and is often used in immunological research in mammals and teleosts. However, the immune responses initiated by R848 through the TLR7/8 pathway in response to bacterial infection remain largely unexplored in teleosts. In the current study, we investigated the antibacterial response and the participating signaling pathway initiated by R848 in golden pompano (Trachinotus ovatus). We found that R848 could stimulate the proliferation of head kidney lymphocytes (HKLs) in a dose-dependent manner, enhance the survival rate of HKLs, and inhibit the replication of bacteria in vivo. However, these effects induced by R848 were significantly reduced when chloroquine (CQ) was used to blocked endosomal acidification. Additionally, an in vivo study showed that R848 strengthened the antibacterial immunity of fish through a TLR7/8 and Myd88-dependent signaling pathway. A cellular experiment showed that Pepinh-MYD (a Myd88 inhibitor) significantly reduced the R848-mediated proliferation and survival of HKLs. Luciferase activity analysis showed that R848 enhanced the nuclear factor kappa B (NF-κB) activity, whereas this activity was reduced when CQ and Pepinh-MYD were present. Additionally, when an NF-κB inhibitor was present, the R848-mediated pro-proliferative and pro-survival effects on HKLs were significantly diminished. An in vivo study showed that knockdown of TLR7, TLR8, and Myd88 expression in golden pompano via siRNA following injection of R848 resulted in increased bacterial dissemination and colonization in fish tissues compared to that of fish injection of R848 alone, suggesting that R848-induced antibacterial immunity was significantly reduced. In conclusion, these results indicate that R848 plays an essential role in the antibacterial immunity of golden pompano via the TLR7/8-Myd88-NF-κB- signaling pathway.
Highlights
R848 (Resiquimod) is an immune response modifier that is known for its potential antiviral activity (1, 2)
The results showed that the number of bacteria incubated with R848 was similar to that incubated with the control, suggesting that R848 did not have direct bactericidal effects
The results revealed that in all the examined tissues, E. tarda infection was extremely significantly decreased in the fish treated with R848 compared to the fish in the control group at each sampling time point
Summary
R848 (Resiquimod) is an immune response modifier that is known for its potential antiviral activity (1, 2). R848 affects antiviral activity by reducing viral shedding and viral reoccurrence (1–4). R848 is recognized by toll-like receptor (TLR) 7 and TLR8, synergistically activates immune cells, and induces an environment of T helper (Th) 1 immune responses (5–8). It acts as a selective activating ligand for both TLR7 and TLR8 in humans but only TLR7 in mice (9, 10). R848 activates pDCs (plasmacytoid dendritic cells), monocytes, and macrophages through TLR7/8 to secrete a variety of cytokines that mediate innate and acquired immunity (3–6)
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