Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils
✍ Scribed by Zhifang Zhang; Gregory Cherryholmes; Frances Chang; David M. Rose; Ingrid Schraufstatter; John E. Shively
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 469 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0014-2980
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
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.