The Syk Tyrosine Kinase Is Required for Skin Inflammation in an In Vivo Mouse Model Of Epidermolysis Bullosa Acquisita

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2017 Jun 4

PMID 28576735

Citations 20

Authors

Tamas Nemeth

Oana Virtic

Cassian Sitaru

Attila Mocsai

Affiliations

Soon will be listed here.

Abstract

The inflammatory form of epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen (C7), a component of the dermal-epidermal junction. We have previously shown that myeloid Src family kinases mediate skin inflammation triggered by anti-C7 antibodies. Here we identify the Syk tyrosine kinase as a critical component of autoantibody-induced skin inflammation downstream of Src family kinases. Immobilized C7-anti-C7 immune complexes triggered neutrophil activation and Syk phosphorylation in a Src family kinase-dependent manner. Bone marrow chimeric mice lacking Syk in their hematopoietic compartment were completely protected from skin inflammation triggered by anti-C7 antibodies despite normal circulating anti-C7 levels. Syk deficiency abrogated the accumulation of CXCL2, IL-1β, and leukotriene B at the site of inflammation and resulted in defective in vivo neutrophil recruitment. Syk neutrophils had a normal intrinsic migratory capacity but failed to release CXCL2 or leukotriene B upon activation by immobilized C7-anti-C7 immune complexes, indicating a role for Syk in the amplification of the inflammation process. These results identify Syk as a critical component of skin inflammation in a mouse model of epidermolysis bullosa acquisita and as a potential therapeutic target in epidermolysis bullosa acquisita and other mechanistically related inflammatory skin diseases such as bullous pemphigoid.

Citing Articles

Monocyte populations are involved in the pathogenesis of experimental epidermolysis bullosa acquisita.

Akbarzadeh R, Czyz C, Thomsen S, Schilf P, Murthy S, Sadik C Front Immunol. 2023; 14:1241461.

PMID: 38116004 PMC: 10728641. DOI: 10.3389/fimmu.2023.1241461.

The selective inhibition of the Syk tyrosine kinase ameliorates experimental autoimmune arthritis.

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Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models.

Futosi K, Nemeth T, Horvath A, Abram C, Tusnady S, Lowell C J Exp Med. 2023; 220(7).

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Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases.

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PMID: 36248903 PMC: 9555174. DOI: 10.3389/fimmu.2022.865241.

References

Kertesz Z, Gyori D, Kormendi S, Fekete T, Kis-Toth K, Jakus Z . Phospholipase Cγ2 is required for basal but not oestrogen deficiency-induced bone resorption. Eur J Clin Invest. 2011; 42(1):49-60. PMC: 3266491. DOI: 10.1111/j.1365-2362.2011.02556.x. View

Schmidt E, Zillikens D . Pemphigoid diseases. Lancet. 2012; 381(9863):320-32. DOI: 10.1016/S0140-6736(12)61140-4. View

Baum S, Sakka N, Artsi O, Trau H, Barzilai A . Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014; 13(4-5):482-9. DOI: 10.1016/j.autrev.2014.01.047. View

Futosi K, Fodor S, Mocsai A . Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol. 2013; 17(3):638-50. PMC: 3827506. DOI: 10.1016/j.intimp.2013.06.034. View

Turner M, Mee P, Costello P, Williams O, Price A, Duddy L . Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature. 1995; 378(6554):298-302. DOI: 10.1038/378298a0. View

Nemeth T, Futosi K, Hably C, Brouns M, Jakob S, Kovacs M . Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP: generation and analysis of a novel null mutation in mice. J Immunol. 2010; 185(5):3064-75. PMC: 3064944. DOI: 10.4049/jimmunol.0904163. View

Csorba K, Sesarman A, Oswald E, Feldrihan V, Fritsch A, Hashimoto T . Cross-reactivity of autoantibodies from patients with epidermolysis bullosa acquisita with murine collagen VII. Cell Mol Life Sci. 2010; 67(8):1343-51. PMC: 11115820. DOI: 10.1007/s00018-009-0256-3. View

Zhao M, Trimbeger M, Li N, Diaz L, Shapiro S, Liu Z . Role of FcRs in animal model of autoimmune bullous pemphigoid. J Immunol. 2006; 177(5):3398-405. DOI: 10.4049/jimmunol.177.5.3398. View

Mihai S, Chiriac M, Takahashi K, Thurman J, Holers V, Zillikens D . The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita. J Immunol. 2007; 178(10):6514-21. DOI: 10.4049/jimmunol.178.10.6514. View

10.

Weinblatt M, Genovese M, Ho M, Hollis S, Rosiak-Jedrychowicz K, Kavanaugh A . Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 2014; 66(12):3255-64. DOI: 10.1002/art.38851. View

11.

Jakus Z, Simon E, Balazs B, Mocsai A . Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum. 2010; 62(7):1899-910. PMC: 2972644. DOI: 10.1002/art.27438. View

12.

Nemeth T, Mocsai A . Feedback Amplification of Neutrophil Function. Trends Immunol. 2016; 37(6):412-424. DOI: 10.1016/j.it.2016.04.002. View

13.

Kovacs M, Nemeth T, Jakus Z, Sitaru C, Simon E, Futosi K . The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment. J Exp Med. 2014; 211(10):1993-2011. PMC: 4172222. DOI: 10.1084/jem.20132496. View

14.

Ludwig R . Model systems duplicating epidermolysis bullosa acquisita: a methodological review. Autoimmunity. 2011; 45(1):102-10. DOI: 10.3109/08916934.2011.606451. View

15.

Kulkarni S, Sitaru C, Jakus Z, Anderson K, Damoulakis G, Davidson K . PI3Kβ plays a critical role in neutrophil activation by immune complexes. Sci Signal. 2011; 4(168):ra23. DOI: 10.1126/scisignal.2001617. View

16.

Liu Z, Giudice G, Zhou X, Swartz S, Troy J, Fairley J . A major role for neutrophils in experimental bullous pemphigoid. J Clin Invest. 1997; 100(5):1256-63. PMC: 508303. DOI: 10.1172/JCI119639. View

17.

Mocsai A . Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med. 2013; 210(7):1283-99. PMC: 3698517. DOI: 10.1084/jem.20122220. View

18.

Futosi K, Mocsai A . Tyrosine kinase signaling pathways in neutrophils. Immunol Rev. 2016; 273(1):121-39. DOI: 10.1111/imr.12455. View

19.

Kasperkiewicz M, Schmidt E . Current treatment of autoimmune blistering diseases. Curr Drug Discov Technol. 2009; 6(4):270-80. DOI: 10.2174/157016309789869065. View

20.

Ludwig R, Zillikens D . Pathogenesis of epidermolysis bullosa acquisita. Dermatol Clin. 2011; 29(3):493-501, xi. DOI: 10.1016/j.det.2011.03.003. View