MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation.
The IL-1R family member IL-33R mediates Fcε-receptor-I (FcεRI)-independent activation of mast cells leading to NF-κB activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-α. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany; Sebastian.Drube@med.uni-jena.de.
Sebastian
S
Drube
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Florian
0000-0002-5324-9155
F
Kraft
Institute of Immunology, Technical University Dresden, Medical Faculty Carl Gustav Carus, 01307 Dresden, Germany.
Jan
J
Dudeck
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Anna-Lena
AL
Müller
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Franziska
F
Weber
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Christiane
C
Göpfert
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Isabel
I
Meininger
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Mandy
0000-0001-8850-6409
M
Beyer
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Ingo
I
Irmler
Department of Gynecology, Jena University Hospital-Friedrich Schiller University, 07743 Jena, Germany.
Norman
0000-0002-7012-483X
N
Häfner
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany; and.
Dagmar
D
Schütz
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany; and.
Ralf
R
Stumm
Department of Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
Tatiana
T
Yakovleva
Department of Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
Matthias
0000-0002-4944-4652
M
Gaestel
Institute of Immunology, Technical University Dresden, Medical Faculty Carl Gustav Carus, 01307 Dresden, Germany.
Anne
0000-0002-1311-9620
A
Dudeck
Institute of Immunology, Jena University Hospital, 07743 Jena, Germany.
Thomas
T
Kamradt
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D000067596:Interleukin-33 / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology*; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011565:Psoriasis / Q000276:immunology*; D012867:Skin / Q000276:immunology*; D000099190:MAP-Kinase-Activated Kinase 2
D018836:Inflammation Mediators; D000067596:Interleukin-33; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3