Regulation of the interferon‐α production induced by RNA‐containing immune complexes in plasmacytoid dendritic cells

Abstract

Objective. Interferon-␣ (IFN␣) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFN␣ production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.Methods. Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFN␣ production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E 2 (PGE 2 ), reactive oxygen species (ROS), or the cytokines IFN␣2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor ␣ (TNF␣) were explored.Results. Monocytes inhibited IFN␣ production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFN␣ production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFN␣2b/GM-CSF increased their IFN␣ production. RNA-containing ICs caused production of ROS, PGE 2 , and TNF␣, especially in monocytes. These mediators and IL-10 suppressed IFN␣ production in PBMC cultures, with ROS and PGE 2 also inhibiting IFN␣ production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFN␣2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.Conclusion. IFN␣ production induced by RNAcontaining ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro-and antiinflammatory molecules. This should be considered when designing and applying new therapies.

Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells

“…This increase was even more pronounced than the increase in CD319 among CD56 dim NK cells in PBMC cultures. Consequently, inhibitory cells present in the PBMC population may suppress the upregulation of SLAM molecules on NK cells, possibly via the release of reactive oxygen species, TNF-a, and PGE 2 , which suppress NK cell function (14). We also noted that IFN-a and IL-12/IL-18 could upregulate CD319 on CD56 dim NK cells, representing an interesting mechanism whereby inflammation may augment NK cell recognition of, and activation by, hematopoietic cells.…”

“…Previous studies showed that NK cells interact with pDCs to potently enhance IFN-a production upon stimulation with viruses, synthetic oligonucleotides, or RNA-containing ICs (RNA-ICs) (13)(14)(15). Mechanistically, NK cells promoted RNA-IC-induced IFN-a secretion by pDCs via soluble factors, such as MIP-1b, and via LFA-1-dependent cell-cell interactions.…”

“…3A). Because the stimulation of pDCs by these ICs is strongly promoted by NK cells (14,15), we proceeded to investigate the regulation of CD319 and CD229 in cocultures of pDCs and NK cells. Notably, the addition of NK cells restored the upregulation of CD319 and CD229 on pDCs (Fig.…”

“…Because monocytes inhibit IFN-a production by pDCs (14), PBMCs were depleted of monocytes before stimulation with RNA-ICs. After stimulation, pDCs were evaluated for intracellular IFN-a and SLAM family member expression.…”

The Role of B-Cells and B-Cell Targeted Therapies in Lupus Nephritis

“…29 Regardless of the mechanism of upregulation of type I IFN, once increased it induces upregulation of TLRs in B cells and subsequent maturation into IgGsecreting plasma cells. 30,31 …”