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 - Funding Information:
We acknowledge Drs. M. Radhakrishna Pillai, T. R. Santhoshkumar, and Ruby John Anto for sharing reagents, Eugene Y. Kim for technical discussions and Jeremy Allegood for LC‐MS analysis. Abgenex, India for providing TLR7 and TLR9 antibodies. Expressing our gratitude to the personnel of FACS core facility and Bio‐imaging facility for their excellent technical assistance and Animal research facility for maintaining the mouse colony. SM and MBL acknowledge senior research fellowships from the Indian Council of Medical Research and University Grant Commission, respectively. SM acknowledges doctoral advisory committee for their valuable suggestions. The work is supported US National Institute of Health grant R01GM043880 (to S.S), a fast track grant from Department of Science and Technology, Government of India (No. SR/FT/LS‐159/2012) and grand‐in‐aid scheme of Council for Scientific and Industrial Research (No.37 (1720)/18/EMR‐II) and in part by faculty start‐up grant and DBT‐Ramalingaswami fellowship (No.BT/RLF/Reentry/38/2011) to KBH
Funding Information:
We acknowledge Drs. M. Radhakrishna Pillai, T.?R.?Santhoshkumar, and Ruby John Anto for sharing reagents, Eugene Y. Kim for technical discussions and Jeremy Allegood for LC-MS analysis. Abgenex, India for providing TLR7 and TLR9?antibodies. Expressing our gratitude to the personnel of FACS core facility and Bio-imaging facility for their excellent technical assistance and Animal research facility for maintaining the mouse colony. SM and MBL acknowledge senior research fellowships from the Indian Council of Medical Research and University Grant Commission, respectively. SM acknowledges doctoral advisory committee for their valuable suggestions. The work is supported US National Institute of Health grant R01GM043880 (to S.S), a fast track grant from Department of Science and Technology, Government of India (No. SR/FT/LS-159/2012) and grand-in-aid scheme of Council for Scientific and Industrial Research (No.37 (1720)/18/EMR-II) and in part by faculty start-up grant and DBT-Ramalingaswami fellowship (No.BT/RLF/Reentry/38/2011) to KBH
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
UR - http://www.scopus.com/inward/record.url?scp=85078665376&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078665376&partnerID=8YFLogxK
U2 - 10.1096/fj.201902847R
DO - 10.1096/fj.201902847R
M3 - Article
C2 - 31971297
AN - SCOPUS:85078665376
VL - 34
SP - 4329
EP - 4347
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 3
ER -