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Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation.  (2013)

Authors:
Lamagna C;Scapini P;van Ziffle JA;DeFranco AL;Lowell CA
Title:
Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation.
Year:
2013
Type of item:
Articolo in Rivista
Tipologia ANVUR:
Articolo su rivista
Language:
Inglese
Referee:
No
Name of journal:
Proceedings of the National Academy of Sciences of the United States of America
ISSN of journal:
0027-8424
N° Volume:
110
Number or Folder:
35
Page numbers:
E3311-E3320
Keyword:
Lyn tyrosine kinase; conditional dendritic cell mutants; interleukin 1 signaling; lipopolysacchride signaling
Short description of contents:
Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells (DCs), triggers lupus-like disease in mice, characterized by autoantibody production and renal immune complex deposition leading to chronic glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The hyperactive B-cell responses are thought to underlie the development of autoimmunity in this model. Lyn-deficient mice also manifest significant myeloexpansion. To test the contribution of different immune cell types to the lupus-like disease in this model, we generated a lyn(flox/flox) transgenic mouse strain. To our surprise, when we crossed these mice to Cd11c-cre animals, generating DC-specific deletion of Lyn, the animals developed spontaneous B- and T-cell activation and subsequent production of autoantibodies and severe nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe tissue inflammatory disease, which was not present in the global lyn(-/-) strain. Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor agonists and IL-1β. To test whether dysregulation of these signaling pathways in DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lyn(f/f) Cd11c-cre(+) mice to myd88(f/f) animals, generating double-mutant mice lacking both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we demonstrate that hyperactivation of MyD88-dependent signaling in DCs is sufficient to drive pathogenesis of lupus-like disease, illuminating the fact that dysregulation in innate immune cells alone can lead to autoimmunity.
Product ID:
79850
Handle IRIS:
11562/670159
Deposited On:
February 21, 2014
Last Modified:
August 16, 2021
Bibliographic citation:
Lamagna C;Scapini P;van Ziffle JA;DeFranco AL;Lowell CA, Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. «Proceedings of the National Academy of Sciences of the United States of America» , vol. 110 , n. 352013pp. E3311-E3320

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