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Proinflammatory Proteases Liberate a Discrete High-Affinity Functional FPRL1 (CCR12) Ligand from CCL23^1,2

Zhenhua Miao^3,*, Brett A. Premack^*, Zheng Wei^*, Yu Wang^*, Craig Gerard, Henry Showell, Maureen Howard^*, Thomas J. Schall^* and Robert Berahovich^*

^* ChemoCentryx, Mountain View, CA 94043; and Children’s Hospital, Harvard Medical School, Boston, MA 02115

Most chemokines have been found to bind to and signal through single or highly related chemokine receptors. However, a single chemokine protein, a processed form of the alternatively spliced CCL23 (CK8/MPIF-1) gene product, potently engages both the "classical" chemokine receptor CCR1, as well as FPRL1, a type of pattern recognition receptor on innate immune cells. However, the mechanism by which the alternative form of CCL23 is processed is unknown. In this study, we show that proteases associated with inflammation cleave CCL23 immediately N-terminal to the 18-residue domain encoded by the alternatively spliced nucleotides, resulting in potent CCR1 and FPRL1 activity. The proteases also cleave CCL23 immediately C-terminal to the inserted domain, producing a typical CC chemokine "body" containing even further-increased CCR1 potency and a released 18-aa peptide with full FPRL1 activity but no activity for CCR1. This peptide, which we term SHAAGtide, is by itself an attractant of monocytes and neutrophils in vitro, recruits leukocytes in vivo, and is 50- to 100-fold more potent than all other natural agents posited to act on FPRL1. The appearance of SHAAGtide appears to be transient, however, as the proinflammatory proteases subsequently cleave within the peptide, abolishing its activity for FPRL1. The sequential activation of a transient FPRL1 ligand and a longer-lived CCR1 ligand within a single chemokine may have important consequences for the development of inflammation or the link between innate and adaptive immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health National Institute of Allergy and Infectious Diseases Grant 1 U19 AI056690 (to ChemoCentryx).

² The term CK8 has been used as one of the traditional names for the CCL23 protein, although CK8-1 indicates a variant containing a replacement of Arg²⁵ with an 18-residue peptide, due to alternative splicing of the CCL23 mRNA. Removal of the inhibitory N-terminal domain from CK8 and CK8-1 results in forms beginning with Arg²⁵ (CK8) or with the initial methionine of the inserted peptide (CK8-1). CCL23 = full-length CK8; CCL23 24 = N-terminally truncated CK8; CCL23 = full-length CK8-1; and CCL23 24 = N-terminally truncated CK8-1.

³ Address correspondence and reprint requests to Dr. Zhenhua Miao, ChemoCentryx, 850 Maude Avenue, Mountain View, CA 94043. E-mail address: zmiao{at}chemocentryx.com

⁴ Abbreviations used in this paper: PRR, pattern recognition receptor; fMLP-R or FPR, N-formyl peptide receptor; SAA, serum amyloid A.