CCL17 in Inflammation and Pain

Abstract

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17 E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4 + non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.

Macrophage-Specific MCPIP1/Regnase-1 Attenuates Kidney Ischemia-Reperfusion Injury by Shaping the Local Inflammatory Response and Tissue Regeneration

“…Thus, MCPIP1 might regulate the GM-CSF/IRF4/CCL17 pathway [64]. The chemokine CCL17, which is involved in inflammation and pain, was found to be induced upon treatment of macrophages with GM-CSF via JMJD3-regulated IRF4 signaling [64,65]. Although CCL17 has been reported to drive a pro-fibrotic macrophage phenotype [66], the lack of GM-CSF or IRF4 can also alter macrophage polarization independent of CCL17 [67].…”

Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL‐13

“…In addition, CCR4 signaling via CCL-17 has emerged as an attractive option to treat immune-inflammatory conditions driven by GMCSF. 55 Since nearly all Tregs express and use CCR4 receptor 56 for homing into sites of inflammation, CCR4 receptor blockade while attenuating inflammation may impact homeostatic resolution mechanisms. In this regard, targeting of CCL17 blockade is likely to spare Treg function while modulating Th2 recruitment.…”

“…The role of CCR4 and its ligands CCL17 and CCL22 in allergic disease is well established, 42–48 with the drug discovery efforts focused heavily on receptor antagonism ether with small molecules or mAbs. In addition, CCR4 signaling via CCL‐17 has emerged as an attractive option to treat immune‐inflammatory conditions driven by GMCSF 55 . Since nearly all Tregs express and use CCR4 receptor 56 for homing into sites of inflammation, CCR4 receptor blockade while attenuating inflammation may impact homeostatic resolution mechanisms.…”

The role of interleukin (IL)-23 in regulating pain in arthritis

“…It is possible that there might not be a simple linear sequence of cytokine production and activity, but instead perhaps multiple mediator loops contributing to arthritis pain development [ 22 ]. It was also reported that neuropeptides/neurotrophins, namely NGF, CGRP, and substance P, are required for GM-CSF- and CCL17-driven inflammatory pain [ 47 ]. These mediators have been linked elsewhere with IL-23 biology [ 27 – 33 ] and exploring their link with IL-23 in arthritis pain would be worthwhile.…”