tetano
Editor, Senior Moderator
J Leukoc Biol. 2017 Jul 20. pii: jlb.2A1215-567RR. doi: 10.1189/jlb.2A1215-567RR. [Epub ahead of print]
[h=1]The θ-defensin retrocyclin 101 inhibits TLR4- and TLR2-dependent signaling and protects mice against influenza infection.[/h] Prantner D[SUP]1[/SUP], Shirey KA[SUP]1[/SUP], Lai W[SUP]1[/SUP], Lu W[SUP]2,[/SUP][SUP]3[/SUP], Cole AM[SUP]4[/SUP], Vogel SN[SUP]5[/SUP], Garzino-Demo A[SUP]1,[/SUP][SUP]3,[/SUP][SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Despite widespread use of annual influenza vaccines, seasonal influenza-associated deaths number in the thousands each year, in part because of exacerbating bacterial superinfections. Therefore, discovering additional therapeutic options would be a valuable aid to public health. Recently, TLR4 inhibition has emerged as a possible mechanism for protection against influenza-associated lethality and acute lung injury. Based on recent data showing that rhesus macaque θ-defensins could inhibit TLR4-dependent gene expression, we tested the hypothesis that a novel θ-defensin, retrocyclin (RC)-101, could disrupt TLR4-dependent signaling and protect against viral infection. In this study, RC-101, a variant of the humanized θ-defensin RC-1, blocked TLR4-mediated gene expression in mouse and human macrophages in response to LPS, targeting both MyD88- and TRIF-dependent pathways. In a cell-free assay, RC-101 neutralized the biologic activity of LPS at doses ranging from 0.5 to 50 EU/ml, consistent with data showing that RC-101 binds biotinylated LPS. The action of RC-101 was not limited to the TLR4 pathway because RC-101 treatment of macrophages also inhibited gene expression in response to a TLR2 agonist, Pam3CSK4, but failed to bind that biotinylated agonist. Mouse macrophages infected in vitro with mouse-adapted A/PR/8/34 influenza A virus (PR8) also produced lower levels of proinflammatory cytokine gene products in a TLR4-independent fashion when treated with RC-101. Finally, RC-101 decreased both the lethality and clinical severity associated with PR8 infection in mice. Cumulatively, our data demonstrate that RC-101 exhibits therapeutic potential for the mitigation of influenza-related morbidity and mortality, potentially acting through TLR-dependent and TLR-independent mechanisms.
? Society for Leukocyte Biology.
[h=4]KEYWORDS:[/h] signal transduction; cytokine regulation; inflammation; innate immunity
PMID: 28729359 DOI: 10.1189/jlb.2A1215-567RR
[h=1]The θ-defensin retrocyclin 101 inhibits TLR4- and TLR2-dependent signaling and protects mice against influenza infection.[/h] Prantner D[SUP]1[/SUP], Shirey KA[SUP]1[/SUP], Lai W[SUP]1[/SUP], Lu W[SUP]2,[/SUP][SUP]3[/SUP], Cole AM[SUP]4[/SUP], Vogel SN[SUP]5[/SUP], Garzino-Demo A[SUP]1,[/SUP][SUP]3,[/SUP][SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Despite widespread use of annual influenza vaccines, seasonal influenza-associated deaths number in the thousands each year, in part because of exacerbating bacterial superinfections. Therefore, discovering additional therapeutic options would be a valuable aid to public health. Recently, TLR4 inhibition has emerged as a possible mechanism for protection against influenza-associated lethality and acute lung injury. Based on recent data showing that rhesus macaque θ-defensins could inhibit TLR4-dependent gene expression, we tested the hypothesis that a novel θ-defensin, retrocyclin (RC)-101, could disrupt TLR4-dependent signaling and protect against viral infection. In this study, RC-101, a variant of the humanized θ-defensin RC-1, blocked TLR4-mediated gene expression in mouse and human macrophages in response to LPS, targeting both MyD88- and TRIF-dependent pathways. In a cell-free assay, RC-101 neutralized the biologic activity of LPS at doses ranging from 0.5 to 50 EU/ml, consistent with data showing that RC-101 binds biotinylated LPS. The action of RC-101 was not limited to the TLR4 pathway because RC-101 treatment of macrophages also inhibited gene expression in response to a TLR2 agonist, Pam3CSK4, but failed to bind that biotinylated agonist. Mouse macrophages infected in vitro with mouse-adapted A/PR/8/34 influenza A virus (PR8) also produced lower levels of proinflammatory cytokine gene products in a TLR4-independent fashion when treated with RC-101. Finally, RC-101 decreased both the lethality and clinical severity associated with PR8 infection in mice. Cumulatively, our data demonstrate that RC-101 exhibits therapeutic potential for the mitigation of influenza-related morbidity and mortality, potentially acting through TLR-dependent and TLR-independent mechanisms.
? Society for Leukocyte Biology.
[h=4]KEYWORDS:[/h] signal transduction; cytokine regulation; inflammation; innate immunity
PMID: 28729359 DOI: 10.1189/jlb.2A1215-567RR