n‐Nonanoyl‐CCL14 (NNY‐CCL14), a novel inhibitor of allergic airway inflammation is a partial agonist of human CCR2

Abstract

This study demonstrates that NNY-CCL14 is a partial agonist of CCR2, inhibiting responses of monocytes to the CCR2-selective ligand CCL2. NNY-CCL14 attenuates CCR2-mediated responses by rapidly desensitizing the receptor and preventing chemotaxis, although it is able to induce calcium mobilization but does not lead to CCR2 internalization. Hence this study provides further insights into the possible mechanisms of action of NNY-CCL14, which interacts with multiple chemokine receptors inhibiting the migration and activation of different cell populations involved, thus acting as a potential therapeutic compound to alleviate allergic inflammation.

CCR1- and CCR5-mediated inactivation of leukocytes by a nonglycosaminoglycan (non-GAG)-binding variant of n-Nonanoyl-CCL14 (NNY-CCL14)

“…The in vivo inhibitory effects of NNY-CCL14 in murine models have been assigned to its interaction with CCR1 and CCR5. Therefore, our previous studies validate NNY-CCL14 as a potential therapeutic for the alleviation of allergic airway inflammation [17,18,21].…”

“…Various strategies proposed to target chemokine receptors include peptide-chemokine receptor antagonists, such as Met-CCL5, CCL11 , and I-Tac/E0H1A [16], and lipophilic nonpeptide compounds, i.e., small molecules that may be piperidine or pyrrolidine derivatives [16]. More recently, several strategies for using chemokine-derived agonists for anti-inflammatory therapy have been proposed [17][18][19][20][21].…”

“…In previous studies [17,18,21], the proposed strategy of treating airway inflammation by preventing cellular recruitment via inactivation of chemokine receptors on inflammatory cells before they extravasate was substantiated. The compound NNY-CCL14 [21] is an N-terminally truncated, modified derivative of the naturally occurring chemokine CCL14(9-74) [22].…”

“…It is resistant to degradation by the peptidase CD26/dipeptidyl aminopeptidase IV, which is found abundantly in blood plasma and tissues and on the cell surface of various cell types [21]. Moreover, it acts as an agonistic inactivator of CCR1, CCR2, CCR3, and CCR5 by desensitizing these receptors to further stimulation by natural ligands and internalizing these receptors from the cell surface, subsequently inactivating effector cells [17,18,21]. In addition, systemic administration of NNY-CCL14 significantly abrogates AHR and accumulation of lymphocytes and eosinophils in broncoalveolar lavage in a murine model of allergic inflammation [18].…”

Selective Chemokine Receptor-Targeted Depletion of Pathological Cells as A Therapeutic Strategy for Inflammatory, Allergic and Autoimmune Diseases

“…This approach is the subject of many recent thorough reviews on chemokine receptor antagonists and is only briefly discussed here [63,136,137]. Chemokine receptor blocking agents in development include small molecule antagonists, N-Terminal modified chemokine ligand antagonists and receptor blocking antibodies [63,136,[138][139][140]; Table 6. Despite over 12 years in development, Maraviroc is the only small molecule antagonist that has been approved by the FDA [141]; Table 6.…”