Antimicrobial cathelicidin peptide LL-37 inhibits the LPS/ATP-induced pyroptosis of macrophages by dual mechanism.
Pyroptosis is a caspase-1 dependent cell death, associated with proinflammatory cytokine production, and is considered to play a crucial role in sepsis. Pyroptosis is induced by the two distinct stimuli, microbial PAMPs (pathogen associated molecular patterns) and endogenous DAMPs (damage associated molecular patterns). Importantly, cathelicidin-related AMPs (antimicrobial peptides) have a role in innate immune defense. Notably, human cathelicidin LL-37 exhibits the protective effect on the septic animal models. Thus, in this study, to elucidate the mechanism for the protective action of LL-37 on sepsis, we utilized LPS (lipopolysaccharide) and ATP (adenosine triphosphate) as a PAMP and a DAMP, respectively, and examined the effect of LL-37 on the LPS/ATP-induced pyroptosis of macrophage-like J774 cells. The data indicated that the stimulation of J774 cells with LPS and ATP induces the features of pyroptosis, including the expression of IL-1β mRNA and protein, activation of caspase-1, inflammasome formation and cell death. Moreover, LL-37 inhibits the LPS/ATP-induced IL-1β expression, caspase-1 activation, inflammasome formation, as well as cell death. Notably, LL-37 suppressed the LPS binding to target cells and ATP-induced/P2X7-mediated caspase-1 activation. Together these observations suggest that LL-37 potently inhibits the LPS/ATP-induced pyroptosis by both neutralizing the action of LPS and inhibiting the response of P2X7 to ATP. Thus, the present finding may provide a novel insight into the modulation of sepsis utilizing LL-37 with a dual action on the LPS binding and P2X7 activation.
Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Zhongshuang
Z
Hu
Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Taisuke
T
Murakami
Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Kaori
K
Suzuki
Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Hiroshi
H
Tamura
Department of Bacteriology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Kyoko
K
Kuwahara-Arai
Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Toshiaki
T
Iba
Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Isao
I
Nagaoka
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism; D054804:Cathelicidins / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020170:Caspase 1