Immune response CCR3 signaling in eosinophils
CCR3 signaling in eosinophils
Human eosinophils are key effector cells implicated in a number of chronicinflammatory reactions, associated with bronchial asthma, allergic-inflammatory diseasesand parasitic infections. Chemoattractants/chemokines, generated at the affected sites,promote migration of eosinophils from vasculature into tissue. Chemotactic response ofeosinophils is mostly mediated by CC Chemokine Receptor-3 ( CCR3 ), a member ofG-protein-coupled receptor family, which activates G-protein alpha-i family [1].
Chemokines of the eotaxin group ( Eotaxin, Eotaxin-2, andEotaxin-3 ), acting exclusively via CCR3, induce recruitment ofeosinophils to the sites of inflammation [2], [3]. Othereosinophil-activating chemokines (such as CCL5, CCL7, CCL8 andCCL13 ) can signal via CCR3 and play a crucial role in eosinophil migrationin tissues. These chemokines are not selective and can signal via additional receptors[4].
CCR3 recruitment by eotaxins leads to activation of mitogen-activated proteinkinases, ERK2 and p38MAPK [1]. ERK2 is activated ineosinophils via Phosphatidylinositol-3-kinase-gamma ( PI3K class IB )/PDK(PDPK1)/ PKC-zeta/ H-Ras/ c-Raf-1/ MEK1/2kinases (MAPK/ERK) pathway [5], [6]. Although the upstreamsignaling of p38MAPK in the CCR3 pathway is still unclear, small GTPasesRac1 and Rac2, and PAK1 kinase actively participate in it [7], [8]. Activation of ERK2 and p38MAPK mediatesrelease of arachidonic acid by cytosolic phospholipase-A2 ( cPLA2 ).Arachidonic acid contributes to secretion of lipid mediators, includingprostaglandins and leukotrienes, thus leading to inflammatory response [9],[10], [1].
Eosinophils preferentially assemble NADPH oxidase in plasma membrane to generateextracellular reactive oxygen species (ROS). Both Rac1 and Rac2 activatethe normally latent NADPH oxidase complex that is composed of five essential subunits,the membrane-bound cytochrome b558 (a complex of two subunits, p22-phox andgp91-phox ) that associates with cytosolic subunits p47-phox andp67-phox (in a complex with p40-phox ) [11].
Inducible nitric oxide synthase ( iNOS ) expressed in eosinophils can beinfluenced by Rac2, thereby modulating nitric oxide ( NO ) synthesis andinflammatory response [12], [13].
CCR3 also transduces signals eliciting Ca(2+) influx [14].This pathway includes activation of Phospholipase C beta ( PLC-beta ) that isresponsible for the production of the second messengers Diacylglycerol ( DAG ) andInositol Triphosphate ( IP3 ). IP3 binds to IP3 receptor on thesurface of the endoplasmic reticulum and releases Ca(2+). [15].DAG activates protein kinases C (e.g. PKC-alpha ) which are involved inregulation of MAPK/ERK pathway [16], [17].
Small GTPase RhoA and its effector kinase, ROCK2, are activated ineosinophils by eotaxin. Small GTPases signaling plays a key role in the formation ofstress fibers. ROCK2 regulates actin cytoskeleton by inhibiting myosin phosphatase( MLCP ) activity and promoting regulatory function of the myosin-binding subunits( MRLC ), and myosin light chains ( MELC ) to facilitate their binding toMyosin heavy chain. Classical Ca(2+) signaling involves myosin light chainkinase ( MLCK ) activation by Ca(2+)/ Calmodulin complex, leadingto MRLC and MELC phosphorylation. Alternative RhoA pathways, viaROCK/ LIM kinase 2 ( LIMK2 )/ Cofilin or DIA1/Profilin, lead to rearrangement of Actin cytoskeletal and stressfiber formation [18].
CCR3 also activates Hck and FGR kinases, which regulate actinpolymerization via WASP/ Arp2/3 or WASP/ Profilinactivation, leading to the rapid cell shape changes required for cell migration [19].
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