Toll-like receptor 7 (TLR7) and TLR7-mediated production of type I interferons by plasmacytoid dendritic cells (pDCs) are thought to have central roles in systemic lupus erythematosus (SLE). New findings highlight IT1t, a ligand of the chemokine receptor CXCR4, as an inhibitor of type I interferon production by pDCs, and the IT1t binding site on CXCR4 as a potential therapeutic target in SLE.

Credit: Steven Milne/Alamy Stock Photo

Previous studies have shown that a synthetic histamine analogue, clobenpropit, could interact with CXCR4 and inhibit type I interferon production by pDCs. Because clobenpropit also binds histamine receptors, in the new study, the researchers investigated the effects of two CXCR4-specific ligands: AMD3100 (an FDA-approved CXCR4 antagonist) and IT1t (a small amino compound).

The two ligands bind to different sites on CXCR4 and are proposed to have different biological activities. “Interestingly, IT1t is structurally similar to clobenpropit and was, as expected, the only one of these two ligands that could inhibit type I interferon production by pDCs in vitro,” explains corresponding author Jean-Philippe Herbeuval.

In ex vivo tonsil mononuclear cell suspensions, IT1t inhibited TLR7-mediated production of IFNα. Furthermore, IT1t treatment reduced systemic inflammation and autoantibody production, and prevented glomerulonephritis, in a TLR7-dependent mouse model of SLE (pristane-induced lupus).

Treatment with IT1t in vitro also abrogated the production of IFNα by resting and stimulated peripheral blood mononuclear cells from patients with SLE, and normalized the expression of inflammatory gene transcripts in these cells.

“We propose that agonists of CXCR4 could represent a novel class of anti-inflammatory molecules that target CXCR4-positive cells such as pDCs,” says Nikaïa Smith, co-corresponding author on the study.

IT1t treatment reduced systemic inflammation and autoantibody production

The researchers plan to fully characterize the IT1t binding pocket on CXCR4 and the underlying mechanisms of action, to develop new CXCR4 ligands that have an even higher efficiency for blocking type I interferon production than IT1t, and to expand these findings to other autoimmune diseases (such as dermatomyositis).