What does elevated TARC/CCL17 expression tell us about eosinophilic disorders?

Abstract

Eosinophilic disorders encompass a large spectrum of heterogeneous diseases sharing the presence of elevated numbers of eosinophils in blood and/or tissues. Among these disorders, the role of eosinophils can vary widely, ranging from a modest participation in the disease process to the predominant perpetrator of tissue damage. In many cases, eosinophilic expansion is polyclonal, driven by enhanced production of interleukin-5, mainly by type 2 helper cells (Th2 cells) with a possible contribution of type 2 innate lymphoid cells (ILC2s). Among the key steps implicated in the establishment of type 2 immune responses, leukocyte recruitment toward inflamed tissues is particularly relevant. Herein, the contribution of the chemo-attractant molecule thymus and activation-regulated chemokine (TARC/CCL17) to type 2 immunity will be reviewed. The clinical relevance of this chemokine and its target, C-C chemokine receptor 4 (CCR4), will be illustrated in the setting of various eosinophilic disorders. Special emphasis will be put on the potential diagnostic, prognostic, and therapeutic implications related to activation of the TARC/CCL17-CCR4 axis.

Keywords: C-C chemokine receptor 4 (CCR4); CCL17; Eosinophilic disorders; Eosinophils; Hypereosinophilic syndromes; Thymus and activation-regulated chemokine (TARC).

Fig. 1

Identified molecular mechanisms underlying TARC/CCL17 synthesis in selected cell types. Mechanisms involved in induction of TARC/CCL17 synthesis are shown schematically for a human keratinocyte cell lines (HaCaT) and b human monocytes and murine bone marrow–derived macrophages. In HaCaT cells, TNF-α and IFN-γ induce JAK2, p38 MAPK, and Raf-1 activation by phosphorylation after ligation to their dedicated receptors [168, 170]. Subsequently, activated p38 MAPK phosphorylates STAT1 and NFκB, inducing their activation and translocation into the nucleus to trigger TARC/CCL17 synthesis [169]. b In human monocytes and murine macrophages, IL-4 and IL-13-induced phosphorylation and homodimerization of STAT6 (following engagement of both types of IL-4 receptors) triggers TARC/CCL17 expression directly by binding the TARC gene promoter [53, 206]. In addition, activated STAT6 increases transcription of IRF4 and JMJD3, and the latter induces the demethylation of repressive H3K27me3 in the IRF4 promoter region, resulting in enhanced expression of the transcription factor IRF4 that binds directly to the TARC/CCL17 promoter (*the latter mechanism is demonstrated after IL-4 but not IL-13-induction of STAT6) [53]. A similar pathway is involved in GM-CSF-induced TARC/CCL17 transcription, probably through STAT5 activation [52]. Engagement of the type 1 IL-4Rα/common-γ chain heterodimeric receptor by IL-4 also recruits IRS2, inducing its phosphorylation and activation. In turn, IRS2 phosphorylates/activates the PI3K/AKT pathway, ultimately leading to TARC/CCL17 transcription [206]. SOCS1 expression is also induced by IL-4 in healthy human monocytes and has been shown to interact directly with IRS2 and downregulate its activity, through ubiquitination and proteasomal degradation [206]. This figure was created with BioRender.com. IFN interferon, IL interleukin, IRF interferon regulatory factor, IRS insulin receptor substrate, JAK Janus kinase, JMJD3 Jumonji domain-containing protein D3, MAPK mitogen-activated protein kinases, NFκB nuclear factor-kappa B, PI3K phosphatidylinositol 3-kinase, STAT signal transducer and activator of transcription, SOCS suppressor of cytokine signaling protein, TNF tumor necrosis factor, TYK tyrosine kinase