Toll-like receptors (TLRs) play an important role in the host defense against invading microbial pathogens by initiating immune and inflammatory responses. Dysregulation of TLRs has been linked to various inflammatory diseases; as such, phytochemicals targeting TLR activity is a potentially beneficial strategy for treating immune disorders. In this study, we investigated the effect of pheophorbide a (Pa) on TLR signaling via myeloid differentiation primary response (MyD)88- and Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways. Pa suppressed the mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and -12, cyclooxygenase-2, interferon-β, regulated on activation normal T cell expressed and secreted, and inducible nitric oxide synthase (iNOS) in macrophages stimulated with lipopolysaccharide (LPS) or poly(I:C). Pa also blocked nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation induced by TRIF, MyD88, receptor-interacting serine/threonine protein kinase 1, and p65, and inhibited in vitro IκB kinase β and TNF receptor-associated factor family member-associated NF-kappa-B activator-binding kinase (TBK)1 activities. Activation or phosphorylation of NFκB and IκB-α induced by LPS or CpG (TLR9 ligand) was suppressed by Pa, as was interferon regulatory factor (IRF)3 activation induced by TRIF, TBK1, and IRF3. The activation, phosphorylation, and nuclear translocation of IRF3 induced by LPS or poly(I:C) was inhibited by Pa, leading to the suppression of IRF3-dependent gene expression. Importantly, Pa inhibited TNF-α and IL-6 gene expression and liver inflammation, resulting in increased survival of mice with LPS-induced endotoxemia. These results indicate that Pa has therapeutic potential for mitigating sepsis-related inflammation via modulation of TLR signaling.<br/>

Pheophorbide a suppresses toll-like receptor signaling via IKKβ/NFκB/TBK1/IRF3 to improve survival in septic mice

256th National Meeting (2018)

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