Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils.
LL-37, derived from human cathelicidin, stimulates immune responses in neutrophils. Although FPR2 and P2X7 were proposed as LL-37 receptors, we have shown that among 21 neutrophil receptors only CXCR2 was down-regulated by LL-37. LL-37 functions similarly to CXCR2-specific chemokines CXCL1 and CXCL7 in terms of receptor down-regulation and intracellular calcium mobilization on freshly isolated neutrophils. Neutrophils pretreated with CXCL8, a chemokine that binds both CXCR1/2, completely blocked the calcium mobilization in response to LL-37, while LL-37 also partially inhibited (125)I-CXCL8 binding to neutrophils. SB225002, a selective CXCR2 antagonist, blocked LL-37-induced calcium mobilization and migration of neutrophils. LL-37 stimulates calcium mobilization in CXCR2-transfected HEK293 cells, CXCR2(+) THP-1 cells and monocytes, but not in CXCR1-transfected HEK293 cells. WKYMVm peptide (ligand for FPR2) does not block LL-37-stimulated calcium flux in either THP-1 (FPR2(-)) or monocytes (FPR2(high)), further confirming the specificity of LL-37 for CXCR2 and not FPR2. Among all ligands tested (ATP, BzATP, WKYMVm, CXCL1, and LL-37), only LL-37 stimulated migration of monocytes (CXCR2(+) and FPR2(+)) and migration was inhibited by the CXCR2 inhibitor SB225002. Moreover, CXCR2 but not CXCR1 was internalized in LL-37-treated neutrophils. Thus, our data provide evidence that LL-37 may act as a functional ligand for CXCR2 on human neutrophils.
Zhang
Zhifang
Z
Department of Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Cherryholmes
Gregory
G
Chang
Frances
F
Rose
David M
DM
Schraufstatter
Ingrid
I
Shively
John E
JE
D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000276:immunology* / Q000378:metabolism; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D008024:Ligands; D023063:Receptors, Interleukin-8B; D002118:Calcium; D054804:Cathelicidins