Functional Beta2-Integrins Restrict Skin Inflammation In Vivo.
Beta2-integrins and the important integrin regulator kindlin-3 are essential for leukocyte trafficking, but the role of beta2-integrins in regulating inflammation is still incompletely understood. Here, we have investigated skin inflammation in a mouse model where the kindlin-3 binding site in the beta2-integrin has been mutated (TTT/AAA-beta2-integrin knock-in), leading to expressed but dysfunctional integrins. We show that, surprisingly, neutrophil trafficking into the inflamed skin in a contact hypersensitivity model is normal in these mice, although trafficking of T cells and eosinophils into the skin is reduced. Instead, expression of dysfunctional integrins leads to increased mast cell and dendritic cell numbers in the skin, increased inflammatory cytokine production in the inflamed skin in vivo, and in mast cells in vitro. Furthermore, expression of dysfunctional integrins leads to increased dendritic cell activation and migration to lymph nodes and increased Th1 responses in vivo. Therefore, the kindlin-3/integrin interaction is important for trafficking of T cells and eosinophils but not absolutely required for neutrophil trafficking into the inflamed skin. Functional beta2-integrins also have a major role in restricting the immune response in the inflamed skin and lymph nodes in vivo, likely through effects on mast cell and dendritic cell numbers and activation.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Terhi S
TS
Savinko
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Vicky L
VL
Morrison
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Liisa M
LM
Uotila
Finnish Institute of Occupational Health, Systems Toxicology, Helsinki, Finland.
C Henrik J
CHJ
Wolff
Finnish Institute of Occupational Health, Systems Toxicology, Helsinki, Finland.
Harri T
HT
Alenius
Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland. Electronic address: susanna.fagerholm@helsinki.fi.
Susanna C
SC
Fagerholm
D000818:Animals; D018821:CD18 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D012313:RNA / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018821:CD18 Antigens; D016207:Cytokines; D015847:Interleukin-4; D012313:RNA