Immune response - CCR3 signaling in eosinophils

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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:

  1. Kampen GT, Stafford S, Adachi T, Jinquan T, Quan S, Grant JA, Skov PS, Poulsen LK, Alam R
    Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood 2000 Mar 15;95(6):1911-7
  2. Menzies-Gow A, Ying S, Sabroe I, Stubbs VL, Soler D, Williams TJ, Kay AB
    Eotaxin (CCL11) and eotaxin-2 (CCL24) induce recruitment of eosinophils, basophils, neutrophils, and macrophages as well as features of early- and late-phase allergic reactions following cutaneous injection in human atopic and nonatopic volunteers. Journal of immunology (Baltimore, Md. : 1950) 2002 Sep 1;169(5):2712-8
  3. Mayer KL, Stone MJ
    Backbone dynamics of the CC-chemokine eotaxin-2 and comparison among the eotaxin group chemokines. Proteins 2003 Feb 1;50(2):184-91
  4. Sabroe I, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease JE, Collins PD, Williams TJ
    Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 1;162(5):2946-55
  5. Hodgkinson CP, Sale GJ
    Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment. Biochemistry 2002 Jan 15;41(2):561-9
  6. Badewa AP, Heiman AS
    Inhibition of CCL11, CCL24, and CCL26-induced degranulation in HL-60 eosinophilic cells by specific inhibitors of MEK1/MEK2, p38 MAP kinase, and PI 3-kinase. Immunopharmacology and immunotoxicology 2003 May;25(2):145-57
  7. Woo CH, Jeong DT, Yoon SB, Kim KS, Chung IY, Saeki T, Kim JH
    Eotaxin induces migration of RBL-2H3 mast cells via a Rac-ERK-dependent pathway. Biochemical and biophysical research communications 2002 Nov 1;298(3):392-7
  8. Fulkerson PC, Zhu H, Williams DA, Zimmermann N, Rothenberg ME
    CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood 2005 Jul 15;106(2):436-43
  9. Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ
    cPLA2 is phosphorylated and activated by MAP kinase. Cell 1993 Jan 29;72(2):269-78
  10. Gordon RD, Leighton IA, Campbell DG, Cohen P, Creaney A, Wilton DC, Masters DJ, Ritchie GA, Mott R, Taylor IW, Bundell KR, Douglas L, Morten J, Needham M
    Cloning and expression of cystolic phospholipase A2 (cPLA2) and a naturally occurring variant. Phosphorylation of Ser505 of recombinant cPLA2 by p42 mitogen-activated protein kinase results in an increase in specific activity. European journal of biochemistry / FEBS 1996 Jun 15;238(3):690-7
  11. Lacy P, Abdel-Latif D, Steward M, Musat-Marcu S, Man SF, Moqbel R
    Divergence of mechanisms regulating respiratory burst in blood and sputum eosinophils and neutrophils from atopic subjects. Journal of immunology (Baltimore, Md. : 1950) 2003 Mar 1;170(5):2670-9
  12. Ferreira HH, Lodo ML, Martins AR, Kandratavicius L, Salaroli AF, Conran N, Antunes E, De Nucci G
    Expression of nitric oxide synthases and in vitro migration of eosinophils from allergic rhinitis subjects. European journal of pharmacology 2002 May 3;442(1-2):155-62
  13. Kone BC, Kuncewicz T, Zhang W, Yu ZY
    Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. American journal of physiology. Renal physiology 2003 Aug;285(2):F178-90
  14. Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS
    Cloning, expression, and characterization of the human eosinophil eotaxin receptor. The Journal of experimental medicine 1996 May 1;183(5):2349-54
  15. Sano A, Zhu X, Sano H, Mu?oz NM, Boetticher E, Leff AR
    Regulation of eosinophil function by phosphatidylinositol-specific PLC and cytosolic PLA(2). American journal of physiology. Lung cellular and molecular physiology 2001 Oct;281(4):L844-51
  16. Greenaway EC, Cunningham FM, Goode NT
    Differential localization of protein kinase C isotypes in equine eosinophils and neutrophils. Journal of leukocyte biology 2000 Oct;68(4):575-82
  17. Woschnagg C, Venge P, Garcia RC
    The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. Cytokine 2004 Nov 7;28(3):137-48
  18. Adachi T, Vita R, Sannohe S, Stafford S, Alam R, Kayaba H, Chihara J
    The functional role of rho and rho-associated coiled-coil forming protein kinase in eotaxin signaling of eosinophils. Journal of immunology (Baltimore, Md. : 1950) 2001 Oct 15;167(8):4609-15
  19. El-Shazly A, Yamaguchi N, Masuyama K, Suda T, Ishikawa T
    Novel association of the src family kinases, hck and c-fgr, with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. Biochemical and biophysical research communications 1999 Oct 14;264(1):163-70

  1. Kampen GT, Stafford S, Adachi T, Jinquan T, Quan S, Grant JA, Skov PS, Poulsen LK, Alam R
    Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood 2000 Mar 15;95(6):1911-7
  2. Menzies-Gow A, Ying S, Sabroe I, Stubbs VL, Soler D, Williams TJ, Kay AB
    Eotaxin (CCL11) and eotaxin-2 (CCL24) induce recruitment of eosinophils, basophils, neutrophils, and macrophages as well as features of early- and late-phase allergic reactions following cutaneous injection in human atopic and nonatopic volunteers. Journal of immunology (Baltimore, Md. : 1950) 2002 Sep 1;169(5):2712-8
  3. Mayer KL, Stone MJ
    Backbone dynamics of the CC-chemokine eotaxin-2 and comparison among the eotaxin group chemokines. Proteins 2003 Feb 1;50(2):184-91
  4. Sabroe I, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease JE, Collins PD, Williams TJ
    Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 1;162(5):2946-55
  5. Hodgkinson CP, Sale GJ
    Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment. Biochemistry 2002 Jan 15;41(2):561-9
  6. Badewa AP, Heiman AS
    Inhibition of CCL11, CCL24, and CCL26-induced degranulation in HL-60 eosinophilic cells by specific inhibitors of MEK1/MEK2, p38 MAP kinase, and PI 3-kinase. Immunopharmacology and immunotoxicology 2003 May;25(2):145-57
  7. Woo CH, Jeong DT, Yoon SB, Kim KS, Chung IY, Saeki T, Kim JH
    Eotaxin induces migration of RBL-2H3 mast cells via a Rac-ERK-dependent pathway. Biochemical and biophysical research communications 2002 Nov 1;298(3):392-7
  8. Fulkerson PC, Zhu H, Williams DA, Zimmermann N, Rothenberg ME
    CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood 2005 Jul 15;106(2):436-43
  9. Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ
    cPLA2 is phosphorylated and activated by MAP kinase. Cell 1993 Jan 29;72(2):269-78
  10. Gordon RD, Leighton IA, Campbell DG, Cohen P, Creaney A, Wilton DC, Masters DJ, Ritchie GA, Mott R, Taylor IW, Bundell KR, Douglas L, Morten J, Needham M
    Cloning and expression of cystolic phospholipase A2 (cPLA2) and a naturally occurring variant. Phosphorylation of Ser505 of recombinant cPLA2 by p42 mitogen-activated protein kinase results in an increase in specific activity. European journal of biochemistry / FEBS 1996 Jun 15;238(3):690-7
  11. Lacy P, Abdel-Latif D, Steward M, Musat-Marcu S, Man SF, Moqbel R
    Divergence of mechanisms regulating respiratory burst in blood and sputum eosinophils and neutrophils from atopic subjects. Journal of immunology (Baltimore, Md. : 1950) 2003 Mar 1;170(5):2670-9
  12. Ferreira HH, Lodo ML, Martins AR, Kandratavicius L, Salaroli AF, Conran N, Antunes E, De Nucci G
    Expression of nitric oxide synthases and in vitro migration of eosinophils from allergic rhinitis subjects. European journal of pharmacology 2002 May 3;442(1-2):155-62
  13. Kone BC, Kuncewicz T, Zhang W, Yu ZY
    Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. American journal of physiology. Renal physiology 2003 Aug;285(2):F178-90
  14. Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS
    Cloning, expression, and characterization of the human eosinophil eotaxin receptor. The Journal of experimental medicine 1996 May 1;183(5):2349-54
  15. Sano A, Zhu X, Sano H, Mu?oz NM, Boetticher E, Leff AR
    Regulation of eosinophil function by phosphatidylinositol-specific PLC and cytosolic PLA(2). American journal of physiology. Lung cellular and molecular physiology 2001 Oct;281(4):L844-51
  16. Greenaway EC, Cunningham FM, Goode NT
    Differential localization of protein kinase C isotypes in equine eosinophils and neutrophils. Journal of leukocyte biology 2000 Oct;68(4):575-82
  17. Woschnagg C, Venge P, Garcia RC
    The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. Cytokine 2004 Nov 7;28(3):137-48
  18. Adachi T, Vita R, Sannohe S, Stafford S, Alam R, Kayaba H, Chihara J
    The functional role of rho and rho-associated coiled-coil forming protein kinase in eotaxin signaling of eosinophils. Journal of immunology (Baltimore, Md. : 1950) 2001 Oct 15;167(8):4609-15
  19. El-Shazly A, Yamaguchi N, Masuyama K, Suda T, Ishikawa T
    Novel association of the src family kinases, hck and c-fgr, with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. Biochemical and biophysical research communications 1999 Oct 14;264(1):163-70

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