TY - JOUR
T1 - Regulatory role of SphK1 in TLR7/9-dependent type I interferon response and autoimmunity
AU - Mohammed, Sabira
AU - Vineetha, Nalanda S.
AU - James, Shirley
AU - Aparna, Jayasekharan S.
AU - Babu Lankadasari, Manendra
AU - Maeda, Takahiro
AU - Ghosh, Abhirupa
AU - Saha, Sudipto
AU - Li, Quan Zhen
AU - Spiegel, Sarah
AU - Harikumar, Kuzhuvelil B.
N1 - Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro-inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane-induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN-linked autoimmune disorders.
AB - Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro-inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane-induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN-linked autoimmune disorders.
KW - auto-immunity
KW - interferon
KW - plasmacytoid dendritic cells
KW - sphingosine 1-Phosphate
KW - sphingosine kinase
KW - systemic lupus erythematosus
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U2 - 10.1096/fj.201902847R
DO - 10.1096/fj.201902847R
M3 - Article
C2 - 31971297
AN - SCOPUS:85078665376
SN - 0892-6638
VL - 34
SP - 4329
EP - 4347
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -