Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

Philippe Krebs, Karine Crozat, Daniel Popkin, Michael B. Oldstone, Bruce Beutler

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13djinx/jinx mice, in which cytolytic function of NK and CD8+ T cells is impaired. Unc13djinx/jinx mutants infected with lymphochoriomeningitis virus (LCMV) present typical clinical features of HLH, including splenomegaly, elevated serum IFNγ, and anemia. Proteins mediating cell-cell contact, cytokine signaling or Toll-like receptor (TLR) signaling were analyzed. We show that neither the integrin CD18, which is involved in adhesion between antigen-presenting cells and effector T cells, nor tumor necrosis factor (TNF) made nonredundant contributions to the disease phenotype. Disruption of IFNγ signaling reduced immune cell activation in Unc13djinx/jinx mice, but also resulted in uncontrolled viral proliferation and exaggerated release of inflammatory cytokines. Abrogating the function of myeloid differentiation primary response gene 88 (MyD88) in Unc13djinx/jinx mice suppressed immune cell activation and controlled cytokine production in an IL-1 receptor 1 (IL-1R1)-independent way. Our findings implicate MyD88 as the key initiator of myeloid and lymphoid proliferation in HLH, and suggest that blockade of this signaling molecule may reduce immunopathology in patients.

Original languageEnglish (US)
Pages (from-to)6582-6588
Number of pages7
JournalBlood
Volume117
Issue number24
DOIs
StatePublished - Jun 16 2011

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Hemophagocytic Lymphohistiocytosis
T-cells
Cytokines
Chemical activation
T-Lymphocytes
Phenotype
Interleukin-1 Receptors
Toll-Like Receptors
Splenomegaly
Antigen-Presenting Cells
Viruses
Integrins
Anemia
Adhesion
Tumor Necrosis Factor-alpha
Genes
Molecules
Serum
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. / Krebs, Philippe; Crozat, Karine; Popkin, Daniel; Oldstone, Michael B.; Beutler, Bruce.

In: Blood, Vol. 117, No. 24, 16.06.2011, p. 6582-6588.

Research output: Contribution to journalArticle

Krebs, Philippe ; Crozat, Karine ; Popkin, Daniel ; Oldstone, Michael B. ; Beutler, Bruce. / Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. In: Blood. 2011 ; Vol. 117, No. 24. pp. 6582-6588.
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