GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus.
Autoantibodies
Autoimmunity
Growth and differentiation factor 15
Inflammation
Lupus nephritis
Macrophages
Toll-like-receptor
Journal
Journal of innate immunity
ISSN: 1662-8128
Titre abrégé: J Innate Immun
Pays: Switzerland
ID NLM: 101469471
Informations de publication
Date de publication:
2022
2022
Historique:
received:
24
11
2021
accepted:
21
02
2022
pubmed:
21
4
2022
medline:
15
12
2022
entrez:
20
4
2022
Statut:
ppublish
Résumé
Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6lpr/lpr) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15-/- C57BL/6 and lupus-prone C57BL/6lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system.
Identifiants
pubmed: 35443244
pii: 000523991
doi: 10.1159/000523991
pmc: PMC9801254
doi:
Substances chimiques
Ligands
0
Interferon Type I
0
GDF15 protein, human
0
Growth Differentiation Factor 15
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
673-689Informations de copyright
© 2022 The Author(s). Published by S. Karger AG, Basel.
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