Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 Promoter

Abstract

We previously showed in a small group of donors that eosinophils from a subgroup of individuals responded equipotently to CC chemokine ligand (CCL)11/eotaxin and CCL3/macrophage-inflammatory protein-1α in assays of eosinophil shape change (CCL3/macrophage-inflammatory protein-1α-highly responsive (MHR) donors). In this study, we investigated the functional role of CCL3 in eosinophil responses in 73 donors. MHR donors, identified by their eosinophil shape change responses, represented ∼19% of the donor pool. Eosinophils from these donors showed increased eosinophil CCR1 expression and also underwent CCL3-mediated chemotaxis and up-regulation of CD11b. All MHR donors gave a history of atopy-associated diseases. In a further study, we prospectively recruited 110 subjects, subdivided into nonatopics or atopics, and investigated expression of CCR1 and CCR3 on eosinophils, basophils, monocytes, and neutrophils. Eosinophil CCR1 expression was non-normally distributed in atopics, although higher CCR1 expression levels were not predictive of a diagnosis of atopy or atopic disease. We identified the CCR1 promoter and investigated its function. We found a minimal promoter within 177 bp of the transcription start site, and an upstream enhancer region that facilitated expression in leukocyte cell lines. Collectively, these data demonstrate that MHR individuals form an important subgroup that, when associated with a diagnosis of allergic disease, may require tailored therapy to modulate eosinophil recruitment. Identification of a functional CCR1 promoter will facilitate the study of possible genetic determinants underlying this potentially important clinical phenotype.

Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients

“…Experimental investigations have shown eosinophils to constitutively express the chemokine receptors CCR3 and CCR1 (Ponath et al, 1996;Phillips et al, 2003;Elsner et al, 2005), whose ligands include macrophage inflammatory protein (MIP) 1a/CCL3, RANTES, MCP2/CCL8, MCP3, MCP4, eotaxins and mucosa-associated epithelial chemokine (MEC)/CCL28. While chemokines are thought to primarily regulate the migration pattern of eosinophils, they have also been shown to promote eosinophil activation and function (Zimmermann et al, 2003).…”

Expression and Regulation of CCR1 by Airway Smooth Muscle Cells in Asthma

“…The human CCR1 promoter contains several binding sites for stimulatory-protein-1 (Sp1) (27). For this reason, we looked at the potential involvement of this transcription factor in the induction of CCR1 mRNA expression by TNF-␣ and IFN-␥.…”

p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells

“…Both CCR1 and CCR2 are expressed in human monocytes, lymphocytes and eosinophils. Alternation of CCR1 and CCR2 expression, depending on the states of cell activation, is associated with a variety of inflammatory diseases including: multiple sclerosis, bronchial hyper-reactivity, and atopy (Campbell et al, 1999;Trebst et al, 2001;Phillips et al, 2003). Regulatory mechanism of CCR1 and CCR2 expression is required for a variety of signal transduction pathways.…”