Immune response - CCR3 signaling in eosinophils

CCR3 signaling in eosinophils

Human eosinophils are key effector cells implicated in a number of chronic inflammatory reactions, associated with bronchial asthma, allergic-inflammatory diseases and parasitic infections. Chemoattractants/chemokines, generated at the affected sites, promote migration of eosinophils from vasculature into tissue. Chemotactic response of eosinophils is mostly mediated by CC Chemokine Receptor-3 (CCR3), a member of G-protein-coupled receptor family, which activates G-protein alpha-i family [1].

Chemokines of the eotaxin group (Eotaxin, Eotaxin-2, and Eotaxin-3), acting exclusively via CCR3, induce recruitment of eosinophils to the sites of inflammation [2], [3]. Other eosinophil-activating chemokines (such as CCL5, CCL7, CCL8 and CCL13) can signal via CCR3 and play a crucial role in eosinophil migration in tissues. These chemokines are not selective and can signal via additional receptors [4].

CCR3 recruitment by eotaxins leads to activation of mitogen-activated protein kinases, ERK2 and p38MAPK [1]. ERK2 is activated in eosinophils via Phosphatidylinositol-3-kinase-gamma (PI3K class IB)/ PDK(PDPK1)/ PKC-zeta/ H-Ras/ c-Raf-1/ MEK1/2 kinases (MAPK/ERK) pathway [5], [6]. Although the upstream signaling of p38MAPK in the CCR3 pathway is still unclear, small GTPases Rac1 and Rac2, and PAK1 kinase actively participate in it [7], [8]. Activation of ERK2 and p38MAPK mediates release of arachidonic acid by cytosolic phospholipase-A2 (cPLA2). Arachidonic acid contributes to secretion of lipid mediators, including prostaglandins and leukotrienes, thus leading to inflammatory response [1], [9], [10].

Eosinophils preferentially assemble NADPH oxidase in plasma membrane to generate extracellular reactive oxygen species (ROS). Both Rac1 and Rac2 activate the normally latent NADPH oxidase complex that is composed of five essential subunits, the membrane-bound cytochrome b558 (a complex of two subunits, p22-phox and gp91-phox) that associates with cytosolic subunits p47-phox and p67-phox (in a complex with p40-phox) [11].

Inducible nitric oxide synthase (iNOS) expressed in eosinophils can be influenced by Rac2, thereby modulating nitric oxide (NO) synthesis and inflammatory response [12], [13].

CCR3 also transduces signals eliciting Ca(2+) influx [14]. This pathway includes activation of Phospholipase C beta (PLC-beta) that is responsible for the production of the second messengers Diacylglycerol (DAG) and Inositol Triphosphate (IP3). IP3 binds to IP3 receptor on the surface of the endoplasmic reticulum and releases Ca(2+). [15]. DAG activates protein kinases C (e.g. PKC-alpha) which are involved in regulation of MAPK/ERK pathway [16], [17].

Small GTPase RhoA and its effector kinase, ROCK2, are activated in eosinophils by eotaxin. Small GTPases signaling plays a key role in the formation of stress 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 to Myosin heavy chain. Classical Ca(2+) signaling involves myosin light chain kinase (MLCK) activation by Ca(2+)/Calmodulin complex, leading to MRLC and MELC phosphorylation. Alternative RhoA pathways, via ROCK / LIM kinase 2 (LIMK2)/ Cofilin or DIA1/ Profilin, lead to rearrangement of Actin cytoskeletal and stress fiber formation [18].

CCR3 also activates Hck and FGR kinases, which regulate actin polymerization via WASP/ Arp2/3 or WASP / Profilin activation, leading to the rapid cell shape changes required for cell migration [19].

References:

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