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Regulatory role of SphK1 in TLR7/9‐dependent type I interferon response and autoimmunity
Author(s) -
Mohammed Sabira,
Vineetha Nalanda S.,
James Shirley,
Aparna Jayasekharan S.,
Babu Lankadasari Manendra,
Maeda Takahiro,
Ghosh Abhirupa,
Saha Sudipto,
Li QuanZhen,
Spiegel Sarah,
Harikumar Kuzhuvelil B.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902847r
Subject(s) - tlr9 , tlr7 , sphingosine kinase 1 , autoimmunity , interferon , immune system , biology , systemic lupus erythematosus , sphingosine , immunology , microbiology and biotechnology , sphingosine 1 phosphate , receptor , innate immune system , toll like receptor , medicine , gene expression , biochemistry , gene , dna methylation , disease
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.