FIG 10.

LXA4, a potential therapeutic agent against KSHV. (A) The overall anti-inflammatory action of LXA4 in vivo is attributed to its interactions with multiple receptors, including (i) direct activation of ALX as a receptor agonist and (ii) direct activation of the nuclear receptor AhR. (B) Lipoxin modulates hedgehog signaling and adaptive immunity in KSHV-infected cells. Previous work from Sharma-Walia’s lab (17, 25) has shown that the ALX/FPR receptor is vital for LXA4 signaling and that blocking this receptor elevates the levels of NF-κB, ERK, and COX-2. LXA4 downregulates the AKT pathway in KS-IMM cells and KSHV-infected primary endothelial cells. In the present study, we postulate that LXA4 may be an endogenous ligand that facilitates the translocation of AhR into the nucleus, where it heterodimerizes with the AhR nuclear translocator (ARNT). AhR-ARNT induces the transcription of target genes by the recruitment of various components of the transcriptional machinery, such as ATP-dependent chromatin-remodeling components, such as Brg-1 (the mechanism has been explored in other systems but has yet to be proved in KSHV-infected cells). The proposed mechanism of action of LXA4 is based on our two current findings: (i) the interaction of LXA4 with nucleosome complex components possibly mediated by AhR and (ii) the overall decreased expression of Gli-1 in LXA4-treated PEL cells compared to that in untreated PEL cells. LXA4 inhibits Gli-1 expression noncanonically at the cytoplasmic level through AMPK activation (indicated by “1 Cytoplasm”). The AKT pathway is regulated by AMPK and, in turn, regulates the mTOR/S6 kinase 1 pathway. The phosphorylation of Gli-1 at the Thr 1074 site in LXA4-treated PEL cells suggests the direct inhibition of hedgehog signaling mediated through AMPK. LXA4 treatment decreased PD-L1 expression, which is related to a decrease in AKT activation and the associated inflammation in LXA4-treated BCBL-1 cells. LXA4 also inhibits Gli-1 expression noncanonically at the nuclear level (indicated by “2 Nucleus”). LXA4 treatment of KSHV-infected BCBL-1 cell inhibited HDAC expression and increased SMARCB1 expression. SMARCB1 directly interacts with Gli-1 to repress its transcriptional activity. SMARCB1, importantly, regulates RTA epigenetically to initiate and carry viral lytic gene replication and viral progression.