Crucial role of Mer tyrosine kinase in the maintenance of SIGN-R1+ marginal zone macrophages.
Immunol Cell Biol
; 96(3): 298-315, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29345385
ABSTRACT
Mer Tyrosine Kinase receptor (Mer) is involved in anti-inflammatory efferocytosis. Here we report elevated spontaneous germinal center (Spt-GC) responses in Mer-deficient mice (Mer-/- ) that are associated with the loss of SIGN-R1+ marginal zone macrophages (MZMs). The dissipation of MZMs in Mer-/- mice occurs independently of reduced cellularity or delocalization of marginal zone B cells, sinusoidal cells or of CD169+ metallophillic macrophages. We find that MZM dissipation in Mer-/- mice contributes to apoptotic cell (AC) accumulation in Spt-GCs and dysregulation of the GC checkpoint, allowing an expansion of DNA-reactive B cells in GCs. We further observe that bone marrow derived macrophages from Mer-/- mice produce more TNFα, and are susceptible to cell death upon exposure to ACs compared to WT macrophages. Anti-TNFα Ab treatment of Mer-/- mice is, however, unable to reverse MZM loss, but results in reduced Spt-GC responses, indicating that TNFα promotes Spt-GC responses in Mer-/- mice. Contrary to an anti-TNFα Ab treatment, treatment of Mer-/- mice with a synthetic agonist for the transcription factor LXRα rescues a significant number of MZMs in vivo. Our data suggest that Mer-LXRα signaling plays an important role in the differentiation and maintenance of MZMs, which in turn regulate Spt-GC responses and tolerance.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Moléculas de Adesão Celular
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Receptores de Superfície Celular
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Centro Germinativo
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Lectinas Tipo C
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C-Mer Tirosina Quinase
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Macrófagos
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article