Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin.
The response of the skin to harmful environmental agents is shaped decisively by the status of the immune system. Keratinocytes constitutively express and secrete the chemokine-like mediator, macrophage migration inhibitory factor (MIF), more strongly than dermal fibroblasts, thereby creating a MIF gradient in skin. By using global and epidermis-restricted Mif-knockout (Mif-/-and K14-Cre+/tg; Miffl/fl) mice, we found that MIF both recruits and maintains antigen-presenting cells in the dermis/epidermis. The reduced presence of antigen-presenting cells in the absence of MIF was associated with accelerated and increased formation of nonmelanoma skin tumors during chemical carcinogenesis. Our results demonstrate that MIF is essential for maintaining innate immunity in skin. Loss of keratinocyte-derived MIF leads to a loss of control of epithelial skin tumor formation in chemical skin carcinogenesis, which highlights an unexpected tumor-suppressive activity of MIF in murine skin.-Brocks, T., Fedorchenko, O., Schliermann, N., Stein, A., Moll, U. M., Seegobin, S., Dewor, M., Hallek, M., Marquardt, Y., Fietkau, K., Heise, R., Huth, S., Pfister, H., Bernhagen, J., Bucala, R., Baron, J. M., Fingerle-Rowson, G. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin.
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
Tania
T
Brocks
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
Oleg
O
Fedorchenko
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
Nicola
N
Schliermann
Institute of Pathology and Cytology, University Hospital Cologne, Cologne, Germany.
Astrid
A
Stein
Department of Pathology, Stony Brook University, Stony Brook, New York, USA.|Department of Molecular Oncology, Georg-August University, Göttingen Center of Molecular Biosciences, Ernst-Caspari-Haus, Göttingen, Germany.
Ute M
UM
Moll
Department of Medical and Molecular Genetics, School of Medicine, Guy's Hospital, King's College London, London, United Kingdom.
Seth
S
Seegobin
Institute of Biochemistry and Molecular Cell Biology Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Manfred
M
Dewor
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
Michael
M
Hallek
Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Yvonne
Y
Marquardt
Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Katharina
K
Fietkau
Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Ruth
R
Heise
Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Sebastian
S
Huth
Institute of Virology, University Hospital Cologne, Cologne, Germany.
Herbert
H
Pfister
Institute of Biochemistry and Molecular Cell Biology Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.|Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; and.
Juergen
J
Bernhagen
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Richard
R
Bucala
Department of Dermatology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Jens M
JM
Baron
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; g.fingerle-rowson@gmx.de.|Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
Guenter
G
Fingerle-Rowson
D000818:Animals; D000873:Anthracenes / Q000633:toxicity; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010880:Piperidines / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology* / Q000276:immunology*; D012878:Skin Neoplasms / Q000139:chemically induced*
C556780:3-(2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz(a)anthracene; D000873:Anthracenes; D015703:Antigens, CD; D008263:Macrophage Migration-Inhibitory Factors; D010880:Piperidines; D011725:Pyridines; D054387:Receptors, CXCR; C431843:tris(2-pyridylmethyl)amine
CD44; CD74; DMBA/TPA; chemokine; skin carcinogenesis