CCR3 Pathway in Eosinophils
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CCR3 Pathway in Eosinophils

Human eosinophils are crucial effector cells implicated in a number of chronic inflammatory reactions, associated with bronchial asthma, allergic-inflammatory diseases, and parasitic infections (Ref.1). Bronchial asthma is a multifactorial disease characterized clinically by reversible bronchoconstriction leading to shortness of breath. The inflammatory response associated with asthma is characterized by the recruitment of eosinophils from the bronchial microcirculation in response to the regulated local production of chemoattractant molecules (Ref.2). Chemoattractants/chemokines, generated at the involved sites, promote the migration of eosinophils from the vasculature into the tissue. Chemotaxis of eosinophils is the single most important event in the pathogenesis of allergic inflammation (Ref.3).

The chemotactic response of eosinophils is mostly mediated by CCR3 (CC Chemokine Receptor-3), a member of the G protein-coupled, seven-transmembrane receptor family, linked to heterotrimeric G-Proteins. Although its expression was first thought to be limited to eosinophils, CCR3 is now known to be more widely expressed on cells involved in allergic inflammation, such as basophils, macrophages, mast cells, neutrophils, airway epithelial cells, and potentially TH2 T-lymphocytes (Ref.4). Chemokines such as:  Eotaxin, Eotaxin-2, and Eotaxin3 signal exclusively via CCR3 that recruit eosinophils to the site of inflammation and activate them. On the other hand, the potent eosinophil-activating Beta-chemokines: MCP3 (Monocyte Chemotactic Peptide-3), MCP4, and RANTES (Regulated Upon Activation, Normally T-cell Expressed, and Presumably Secreted) can signal via CCR3 and play a crucial role in eosinophil migration in tissue, but are not selective and can signal via additional receptors. Eosinophils express at least three chemokine receptors including CCR3, CCR1, and CXCR2. Of these, CCR3 achieves by far the highest expression levels and is thought to be the major eosinophil chemokine receptor (Ref.5). CCR3 is sensitive to pertussis toxin, indicating its linkage to G-AlphaI (Ref.1).

Eotaxin has been found to have the broadest spectrum of activities of all eosinophil-activating CC chemokines (Ref.6). At sites of inflammation, eosinophils are responsible for tissue damage by the release of ROS (Reactive Oxygen Species) and toxic granule proteins. Moreover, CCR3 recruitment by Eotaxins stimulates a set of downstream signaling pathways, which are responsible for eosinophil chemotaxis, degranulation, and propagation of the inflammatory response through the secretion of cytokines and chemokines (Ref.1).

CCR3 recruitment by Eotaxin activates MAPKs (Mitogen-Activated Protein Kinases):  ERK1/2(Extracellular Signal-Regulated Kinases) and p38 in eosinophils, which are indispensable for eosinophil chemotaxis and degranulation (Ref.3).ERKs are regulated through the PI3K-Gamma (Phosphatidylinositol-3-Kinase-Gamma)-Ras -Raf1-MEKs (MAPK/ERK Kinases) pathway. Although the upstream signal of p38 in the CCR3 pathway is unclear, Rac and PAKs (p21/CDC42/Rac1-Activated Kinases) have an active participation. On the signaling level,  activation of MAPK pathway (ERK2 and p38) mediates arachidonic acid release catalyzed by cytosolic PLA2 (Phospholipase-A2), contributing to the secretion of lipid mediators, including leukotrienes and Prostaglandins, leading to inflammatory responses, prolonged bronchoconstriction and  increased bronchial mucus production. Increased PLA2 activity is also necessary for fMLP (N-formyl-Met-Leu-Phe)-induced eosinophil degranulation to proceed. Both degranulation and chemotaxis involve profound rearrangement of the actin cytoskeleton (Ref.1). CCR3 is also known to transduce signals eliciting Ca2+ influx. This is accomplished by the activation of PLC-Beta (Phospholipase-C-Beta) that is responsible for the production of the second messengers DAG (Diacylglycerol) and IP3 (Inositol Triphosphate) by cleaving PIP2 (Phosphatidylinositol-4,5-Bisphosphate) at the plasma membrane. IP3 binds to IP3R (IP3 Receptor) on the surface of the ER (Endoplasmic Reticulum) and releases Ca2+. DAG activates PKC (Protein Kinase-C), which in turn is involved in the production of ROS, that causes tissue damage. The ERKs are also responsible for ROS production, and the subsequent tissue damage (Ref.3).

Rho is an important target of CCR3 stimulation in eosinophils, having a dichotomy of downstream signaling pathways, namely, Rho-ROCK and Rho-ERK pathways. The p21 G-protein RhoA and its substrates: ROCKs (Rho-associated coiled-coil forming protein kinase) regulate the formation of stress fibers and focal adhesions. The ROCKs (ROCK1 and ROCK2), play a crucial role in actin cytoskeleton reorganization.  ROCK1 activates MLCK (Myosin Light-Chain Kinase), whereas ROCK2  is responsible for the latter through the inhibition of myosin phosphatase or the direct activation of MLCP (Myosin Light Chain Phosphatase) (Ref.3). The actin cytoskeleton reorganization can also be regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myosin/actin filament. Classical calcium signaling pathway involves MLCK activation by calcium-Calm (Calmodulin) complex leading to rearrangement of actin cytoskeleton (Ref.6).

CCR3 provides a mechanism for the selective recruitment of eosinophils into tissue and thus has become an attractive biological target for therapeutic intervention in the spectrum of diseases involving eosinophil-mediated tissue damage (Ref.7). More recently, involvement CCR3 as a co-receptor for HIV1 infection of microglia cells in the central nervous system has been traced out (Ref.5). Its preferential expression by Th2 T-cells has also been demonstrated, suggesting possible roles for CCR3 in the genesis and maintenance of allergic inflammation and the pathogenesis of atopic dermatitis (Ref.8). Moreover, eosinophils are believed to be of major importance in other inflammatory diseases such as connective tissue diseases of unknown origin. Looking into its multiple actions, studies on CCR3 need to be stressed upon for drug development against various diseases.