Immune response - Fc epsilon RI pathway

Fc-epsilon RI pathway

The Fc epsilon RI complex forms a high-affinity cell-surface receptor interaction for the Fc region of antigen-specific immunoglobulin E (IgE) molecules. Fc epsilonRI controls the activation of mast cells and basophils, and participates in IgE-mediated antigen presentation. Fc epsilon RI is the central to the induction and maintenance of an allergic response and may confer physiological protection in parasitic infections. This receptor induces multiple signaling pathways that control the secretion of allergic mediators and induction of cytokine gene transcription, resulting in secretion of molecules such as Interleukins:IL-4, IL-5, IL-6, IL-10, IL-13, INF-Gamma (Interferon-Gamma), TNF-Alpha (tumour-necrosis factor-alpha), GCSF (granulocyte-macrophage colony-stimulating factor) to name few [1].

Human mast cells and basophils express Fc epsilon RI that consists of three subunits -alpha,beta, gamma, and formes tetramer (AlphaBetaGamma2). However, the Fc epsilon RI on the surface of human monocytes consist of alpha and gamma subunits and form a trimeric (AlphaGamma2) complex. The Alpha-chain binding with IgE and the others subunits are essential for downstream signaling [2].

After Fc epsilon RI aggregation by antigen-induced-crosslinking the immunoglobulin E, beta-subunit-associated LYN is activated and phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) in the beta and gamma subunits of Fc epsilon RI. Phosphorylated ITAMs of the beta- and gamma- subunits recruit additional molecules of LYN and SYK. SYK binding to the Fc epsilon RI complex is activated through conformational changes after tyrosine phosphorylation by LYN.

Activated SYK then phosphorylates many substrates, including linker for activation of T Lcells (LAT), SH2-domain-containing leukocyte protein of 76 kDa (SLP76), VAV, GRB2-associated binding protein 2 (GAB2), and Phospholipase C gamma (PLC-gamma), which leads to the activation of several signaling pathways [1], [3].

Phosphorylation of GAB2 result its recruitment to membrane and activation of Phosphatidylinositol 3-kinase (PI3K), which catalyses the synthesis of Phosphatidylinositol-3,4,5-trisphosphate (PIP₃) and thereby stimulates the AKT signaling pathway.

Phosphorylation of LAT results in recruitment of guanine-nucleotide exchange factor SOS complexed to adaptor protein GRB2. SOS activates small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) leading to initiation of H-RAS/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-RAF)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1 and MEK2)/ Mitogen-activated protein kinases 3 and 1 (ERK1 and ERK2) signaling cascade that targets the Elk1 transcription factor. Moreover ERK phosphorylation activates cytosolic Phospholipase A2 (PLA2) contributing to the secretion of leukotrienes and prostaglandins, leading to inflammatory responses [4].

Additionally, phosphorylated stimulated the recruitment of PLC-gamma to the plasma membrane, which becomes a target of BTK (Bruton tyrosine kinase) and SYK. BTK itself becomes activated through phosphorylation by LYN and SYK [5], [6]. LAT associates with both isoforms PLC-gamma 1 and 2, whereas SYK associates with PLC-gamma 2 [7]. Phosphorylated PLC-gamma generates diacylglycerol (DAG) and Inositol-1,4,5-trisphosphate (IP₃) from Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) [8].

DAG activates many isoforms of Protein kinase C (PKC), including PKC-theta. PKC-theta activates I-kappa-B kinase (IKK) resulting in NF-kB activation [9].

IP₃ activates IR3 receptors (IP3R) that results in the release of Ca²⁺ from intracellular storage- endoplasmic reticulum. In the endoplasmic-reticulum, calcium-bound Calmodulin associates with and activates serine/threonine phosphatase Calcineurin. Calcineurin dephosphorylates NFAT family of transcription factors leading to their translocation to the nucleus [10].

Moreover stimilation of the Fc epsilon RI complex induces activation MAP-kinase cascades. SYK activates the downstream c-Jun N-terminal kinase (JNK) via phosphorylation SLP76 and VAV. VAV is exchange factor for small GTPase Rac1 and activates Rac1-PAK2-MEKK1-MKK4/7-JNK cascade. Accordingly, SYK couples the Fc epsilon RI complex to with the JNK cascade [11].

The Fc epsilon RI complex also activates p38 MAP kinase cascade, perhaps via phosphorylation FER tyrosine kinase by LYN. FER can activate p38 via MKK3 and MKK6 [12].

Fc epsilon RI induction of ERK, JNK and p38 MAP kinase cascades result in the activation of transcription factors regulating the AP-1 complex (c-jun, ATF-2) and NF-AT, NF-kB, which are crucial for immune response signaling[13].

References:

1. Kawakami T, Galli SJ
   Regulation of mast-cell and basophil function and survival by IgE. Nature reviews. Immunology 2002 Oct;2(10):773-86
2. Turner H, Kinet JP
   Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 1999 Nov 25;402(6760 Suppl):B24-30
3. Simon M, Vanes L, Geahlen RL, Tybulewicz VL
   Distinct roles for the linker region tyrosines of Syk in FcepsilonRI signaling in primary mast cells. The Journal of biological chemistry 2005 Feb 11;280(6):4510-7
4. Leslie CC
   Regulation of the specific release of arachidonic acid by cytosolic phospholipase A2. Prostaglandins, leukotrienes, and essential fatty acids 2004 Apr;70(4):373-6
5. Mohamed AJ, Nore BF, Christensson B, Smith CI
   Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 1999 Feb;49(2):113-8
6. Kawakami Y, Kitaura J, Hartman SE, Lowell CA, Siraganian RP, Kawakami T
   Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk. Proceedings of the National Academy of Sciences of the United States of America 2000 Jun 20;97(13):7423-8
7. Draberova L, Dudkova L, Boubelik M, Tolarova H, Smid F, Draber P
   Exogenous administration of gangliosides inhibits Fc epsilon RI-mediated mast cell degranulation by decreasing the activity of phospholipase C gamma. Journal of immunology (Baltimore, Md. : 1950) 2003 Oct 1;171(7):3585-93
8. Tkaczyk C, Beaven MA, Brachman SM, Metcalfe DD, Gilfillan AM
   The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. The Journal of biological chemistry 2003 Nov 28;278(48):48474-84
9. Altman A, Villalba M
   Protein kinase C-theta (PKCtheta): it's all about location, location, location. Immunological reviews 2003 Apr;192:53-63
10. Rusnak F, Mertz P
    Calcineurin: form and function. Physiological reviews 2000 Oct;80(4):1483-521
11. Kawakami Y, Hartman SE, Holland PM, Cooper JA, Kawakami T
    Multiple signaling pathways for the activation of JNK in mast cells: involvement of Bruton's tyrosine kinase, protein kinase C, and JNK kinases, SEK1 and MKK7. Journal of immunology (Baltimore, Md. : 1950) 1998 Aug 15;161(4):1795-802
12. Craig AW, Greer PA
    Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells. Molecular and cellular biology 2002 Sep;22(18):6363-74
13. Lorentz A, Klopp I, Gebhardt T, Manns MP, Bischoff SC
    Role of activator protein 1, nuclear factor-kappaB, and nuclear factor of activated T cells in IgE receptor-mediated cytokine expression in mature human mast cells. The Journal of allergy and clinical immunology 2003 May;111(5):1062-8