TY - JOUR
T1 - Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood–brain barrier
AU - Hauptmann, Judith
AU - Johann, Lisa
AU - Marini, Federico
AU - Kitic, Maja
AU - Colombo, Elisa
AU - Mufazalov, Ilgiz A.
AU - Krueger, Martin
AU - Karram, Khalad
AU - Moos, Sonja
AU - Wanke, Florian
AU - Kurschus, Florian C.
AU - Klein, Matthias
AU - Cardoso, Silvia
AU - Strauß, Judith
AU - Bolisetty, Subhashini
AU - Lühder, Fred
AU - Schwaninger, Markus
AU - Binder, Harald
AU - Bechman, Ingo
AU - Bopp, Tobias
AU - Agarwal, Anupam
AU - Soares, Miguel P.
AU - Regen, Tommy
AU - Waisman, Ari
PY - 2020/10/1
Y1 - 2020/10/1
N2 - The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood–brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
AB - The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood–brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
UR - http://www.scopus.com/inward/record.url?scp=85087712908&partnerID=8YFLogxK
U2 - 10.1007/s00401-020-02187-x
DO - 10.1007/s00401-020-02187-x
M3 - Journal articles
C2 - 32651669
AN - SCOPUS:85087712908
SN - 0001-6322
VL - 140
SP - 549
EP - 567
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -