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Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus
Author(s) -
Mohammed Sabira,
Vineetha Nalanda S.,
James Shirley,
Aparna Jayasekharan S.,
Lankadasari Manendra Babu,
Allegood Jeremy C.,
Li Quan-Zhen,
Spiegel Sarah,
Harikumar Kuzhuvelil B.
Publication year - 2019
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.201802535r
Subject(s) - systemic lupus erythematosus , tlr7 , sphingosine kinase , sphingosine , axl receptor tyrosine kinase , immunology , plasmacytoid dendritic cell , efferocytosis , sphingosine kinase 1 , autoimmune disease , autoimmunity , biology , dendritic cell , cancer research , immune system , sphingosine 1 phosphate , medicine , microbiology and biotechnology , tyrosine kinase , innate immune system , signal transduction , macrophage , disease , biochemistry , receptor , jak stat signaling pathway , antibody , toll like receptor , in vitro
ABSTRACT Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine‐1‐phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane‐induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC‐specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS‐like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane‐induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane‐induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.—Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C, Li, Q.‐Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus. FASEB J. 33, 7061–7071 (2019). www.fasebj.org