Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs

• Published in: Nature communications Vol. 9; no. 1; pp. 1 - 14
• Main Authors: Pellefigues, Christophe, Dema, Barbara, Lamri, Yasmine, Saidoune, Fanny, Chavarot, Nathalie, Lohéac, Charlotte, Pacreau, Emeline, Dussiot, Michael, Bidault, Caroline, Marquet, Florian, Jablonski, Mathieu, Chemouny, Jonathan M., Jouan, Fanny, Dossier, Antoine, Chauveheid, Marie-Paule, Gobert, Delphine, Papo, Thomas, Karasuyama, Hajime, Sacré, Karim, Daugas, Eric, Charles, Nicolas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/1; 14/63; 38/71; 631/250/2504; 631/250/2520; 64/60; 692/699/1585/1614; 82/80; Accumulation; Adaptive immunology; Animal models; Autoantibodies; Autocrine signalling; Autoimmune diseases; Blood levels; Chronic conditions; CXCR4 protein; Human health and pathology; Humanities and Social Sciences; Immunology; Kidneys; Leukocytes (basophilic); Life Sciences; Lupus; Lupus nephritis; Metabolites; multidisciplinary; Nephritis; Organs; Pathophysiology; Prostaglandin D2; Receptors; Renal failure; Rodents; Science; Science (multidisciplinary); Systemic lupus erythematosus; Urology and Nephrology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03129-8

In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D 2 (PGD 2 ) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD 2 receptors (PTGDR) on blood basophils and increased concentration of PGD 2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD 2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD 2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD 2 /PTGDR axis as a ready-to-use therapeutic modality in SLE. In a lupus environment, basophils accumulate in secondary lymphoid organs where they affect pathogenesis by stimulating autoantibody production. Here the authors show this accumulation is driven by PGD2-induced CXCR4 surface expression and trafficking of basophils.