P-glycoprotein acts as an immunomodulator during neuroinflammation.
BACKGROUND
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which autoreactive myelin-specific T cells cause extensive tissue damage, resulting in neurological deficits. In the disease process, T cells are primed in the periphery by antigen presenting dendritic cells (DCs). DCs are considered to be crucial regulators of specific immune responses and molecules or proteins that regulate DC function are therefore under extensive investigation. We here investigated the potential immunomodulatory capacity of the ATP binding cassette transporter P-glycoprotein (P-gp). P-gp generally drives cellular efflux of a variety of compounds and is thought to be involved in excretion of inflammatory agents from immune cells, like DCs. So far, the immunomodulatory role of these ABC transporters is unknown.


RESULTS
Here we demonstrate that P-gp acts as a key modulator of adaptive immunity during an in vivo model for neuroinflammation. The function of the DC is severely impaired in P-gp knockout mice (Mdr1a/1b-/-), since both DC maturation and T cell stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b -/- mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines.


CONCLUSIONS
Our data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherapy.
Kooij
Gijs
G
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Backer
Ronald
R
Koning
Jasper J
JJ
Reijerkerk
Arie
A
van Horssen
Jack
J
van der Pol
Susanne M A
SM
Drexhage
Joost
J
Schinkel
Alfred
A
Dijkstra
Christine D
CD
den Haan
Joke M M
JM
Geijtenbeek
Teunis B H
TB
de Vries
Helga E
HE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D007155:Immunologic Factors / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009420:Nervous System / Q000276:immunology* / Q000473:pathology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma