Autophagy in Dendritic Cells and B Cells Is Critical for the Inflammatory State of TLR7-Mediated Autoimmunity [AUTOIMMUNITY]

Abstract

Individuals suffering from autoimmune disorders possess a hyperactive cellular phenotype where tolerance to self-antigens is lost. Autophagy has been implicated in both the induction and prevention of autoimmunity, and modulators of this cellular recycling process hold high potential for the treatment of autoimmune diseases. In this study, we determine the effects of a loss of autophagy in dendritic cells (DCs), as well as both B cells and DCs, in a TLR7-mediated model of autoimmunity, similar to systemic lupus erythematosus, where both cell types are critical for disease. Although a loss of DC autophagy slowed disease, the combined loss of autophagy in both cell types resulted in a lethal sepsis-like environment, which included tissue inflammation and hyperproduction of inflammasome-associated cytokines. Ablation of B cell signaling reversed this phenotype, indicating that activation of these cells is an essential step in disease induction. Thus, autophagy plays a dichotomous role in this model of disease.

Footnotes

  • This work was supported in part by National Institutes of Health/Clinical and Translational Science Institute Grant UL1TR001064 (to B.T.H.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    ANA
    antinuclear Ab
    APS
    antiphospholipid syndrome
    ATG
    autophagy-related gene
    Bko
    Cd19-cre+/−Atg5f/f
    CL
    cardiolipin
    DBko
    Cd11c-cre+/−Cd19-cre+/−Atg5f/f
    DC
    dendritic cell
    Dko
    Cd11c-cre+/−Atg5f/f
    EMH
    extramedullary hematopoiesis
    ko
    knockout
    LAP
    LC3-associated phagocytosis
    LN
    lymph node
    mDC
    myeloid DC
    mtDNA
    mitochondrial DNA
    MZ
    marginal zone
    PAS
    periodic acid–Schiff
    pDC
    plasmacytoid DC
    SLE
    systemic lupus erythematosus
    tg
    transgenic.
  • Received August 8, 2016.
  • Accepted November 21, 2016.

This content is also available in: Español Português

Do NOT follow this link or you will be banned from the site!