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Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs.

ABSTRACT: 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 D2 (PGD2) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD2 receptors (PTGDR) on blood basophils and increased concentration of PGD2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD2/PTGDR axis as a ready-to-use therapeutic modality in SLE.

SUBMITTER: Pellefigues C

PROVIDER: S-EPMC5820278 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs.

Pellefigues Christophe C Dema Barbara B Lamri Yasmine Y Saidoune Fanny F Chavarot Nathalie N Lohéac Charlotte C Pacreau Emeline E Dussiot Michael M Bidault Caroline C Marquet Florian F Jablonski Mathieu M Chemouny Jonathan M JM Jouan Fanny F Dossier Antoine A Chauveheid Marie-Paule MP Gobert Delphine D Papo Thomas T Karasuyama Hajime H Sacré Karim K Daugas Eric E Charles Nicolas N

Nature communications 20180220 1

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 D2 (PGD2) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD2 receptors (PTGDR) on blood basophils and increased concentration of PGD2 metabolites in plasma. Thro ...[more]

PMID: 29463843

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Project description:BACKGROUND:Aspirin-exacerbated respiratory disease (AERD) differs from aspirin-tolerant disease in part because of eosinophilic tissue infiltration and overexpression of arachidonic acid metabolic pathway components that lead to enhanced secretion of cysteinyl leukotrienes and prostaglandin (PG) D2 observed constitutively and paradoxically in response to aspirin and other COX inhibitors. We have previously demonstrated the capacity of IFN-? to drive cysteinyl leukotriene expression and response. OBJECTIVE:We investigated eosinophils as a source of PGD2 production in patients with AERD. METHODS:Eosinophils were enriched from tissue and peripheral blood obtained from control subjects, patients with aspirin-tolerant disease, and patients with AERD. mRNA was extracted and evaluated for expression of hematopoietic prostaglandin D synthase (hPGDS). Expression of hPGDS protein was confirmed with Western hybridization and immunofluorescence staining. Cells were stimulated with aspirin, and secretion of PGD2 was quantified. CD34+ progenitor cells were isolated and matured into eosinophils in the presence or absence of IFN-? and hPGDS mRNA, and PGD2 release was measured. RESULTS:Gene expression analysis revealed that eosinophils from tissue and blood of patients with AERD display increased levels of hPGDS compared with asthmatic and control samples. Western hybridization confirmed the increase in hPGDS mRNA translated to increased protein expression. Immunofluorescence confirmed mast cells and eosinophils from tissue of patients with AERD and asthma demonstrated hPGDS expression, with higher levels in eosinophils from patients with AERD. Incubation of eosinophils from blood and tissue with aspirin stimulated PGD2 release. IFN-?-matured eosinophil progenitors showed enhanced hPGDS expression and increased levels of PGD2 release at baseline and after aspirin stimulation. CONCLUSIONS:In addition to mast cells, eosinophils represent an important source of PGD2 in patients with AERD and identify a new target for therapeutic intervention.

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Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs.

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Prostaglandin D<sub>2</sub> amplifies lupus disease through basophil accumulation in lymphoid organs.

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Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs.

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Prostaglandin D&lt;sub&gt;2&lt;/sub&gt; amplifies lupus disease through basophil accumulation in lymphoid organs.

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Prostaglandin D<sub>2</sub> amplifies lupus disease through basophil accumulation in lymphoid organs.