Increased PGD₂ signalling in lupus pathogenesis

In systemic lupus erythematosus (SLE), basophils amplify the synthesis of circulating autoreactive antibodies by accumulating in secondary lymphoid organs (SLOs). However, the mechanism by which basophils are recruited to SLOs has remained elusive. Now, Nicolas Charles and colleagues demonstrate in both humans and mice that prostaglandin D₂ (PGD₂) induces CXC-chemokine receptor 4 (CXCR4) externalization on basophils via autocrine signalling through both PGD₂ receptors, which drives their accumulation in SLOs.

PGD₂ receptor antagonists may represent a new, safe and ready-to-use therapeutic modality in SLE by potentially preventing disease flares

The researchers found that basophil surface expression levels of PGD₂ receptors and CXCR4 are increased in patients with active SLE compared with healthy controls, and they subsequently investigated PGD₂ signalling in mouse models of SLE. “We show that repeated PGD₂ injections into lupus-prone mice before disease manifestation accelerated lupus nephritis development by inducing CXCR4-dependent basophil accumulation in SLOs, where they amplify autoantibody production,” says Charles. Moreover, targeting of PGD₂ receptors using specific antagonists — which are in clinical use already, for example, for the treatment of allergic rhinitis and niacin-induced flushing — inhibits basophil redistribution to SLOs and dampens lupus-like disease in two distinct mouse models of SLE. “PGD₂ receptor antagonists may represent a new, safe and ready-to-use therapeutic modality in SLE by potentially preventing disease flares that are due to the basophil-dependent amplification loop of autoantibody production,” explains Charles.

The researchers now plan to study whether the manifestation of lupus-like nephritis in lupus-prone mice can be prevented using PGD₂ receptor antagonists, an approach that aims to assess whether these antagonists may prevent the development of lupus nephritis in patients with SLE. “Furthermore, we plan to set up clinical trials and develop bispecific antagonists targeting both PGD₂ receptors,” concludes Charles.