CCR3 Signaling in Eosinophils


Pathway Description

The chemotactic response of eosinophils is mostly mediated by CC Chemokine Receptor-3 (CCR3), linked to G-Proteins. Chemokines such as: Eotaxin, Eotaxin2, and Eotaxin3 signal exclusively via CCR3 that recruit eosinophils to the site of inflammation and activate them. Eosinophils express at least three chemokine receptors including CCR3, CCR1, and CXCR2. Of these,CCR3 achieves by far the highest expression levels and is the major eosinophil chemokine receptor. CCR3 is sensitive to pertussis toxin, indicating its linkage to G-αI.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.

CCR3 recruitment by eotaxin activates MAPKs ERK1/2 and p38 in eosinophils, which are indispensable for eosinophil chemotaxis and degranulation. ERKs are regulated through the PI3K-γ-Ras-Raf1-MEK-ERK pathway. Although the upstream signal of p38 in the CCR3 pathway is unclear, Rac and PAKs have an active participation. On the signaling level, activation of MAPK pathway (ERK2 and p38) mediates arachidonic acid release catalyzed by cytosolic PLA2,leading to inflammatory responses, prolonged bronchoconstriction and increased bronchial mucus production. CCR3 is also transduce signals eliciting Ca2+ influx. This is accomplished by the activation of PLC-β (Phospholipase-C-β) that is responsible for the production of the second messengers Diacylglycerol (DAG) and Inositol Triphosphate (IP3) by cleaving Phosphatidylinositol-4,5-Bisphosphate (PIP2). IP3 binds to IP3 receptor (IP3R) on the surface of the ER and releases Ca2+. DAG activates PKC, 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.

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 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, whereas ROCK2 is responsible for the latter through the inhibition of myosin phosphatase or the direct activation of MLCP.The actin cytoskeleton reorganization is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myosin/actin filament. Classical calcium signaling pathway involves MLCK activation by calcium-Calmodulin complex leading to rearrangement of actin cytoskeleton.

CCR3 provides a mechanism for the selective recruitment of eosinophils into tissue and is an attractive biological target for therapeutic intervention in the spectrum of diseases involving eosinophil-mediated tissue damage. More recently,involvement CCR3 as a co-receptor for HIV1 infection of microglia cells in the central nervous system has been traced out. Its preferential expression by Th2 T-cells has possible roles for CCR3 in the genesis and maintenance of allergic inflammation and the pathogenesis of atopic dermatitis. Moreover, eosinophils are 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.