Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis

Thomas T. Tapmeier, Nilüfer Rahmioğlu, Jianghai Lin, Lin J, De Leo B, Bianca De Leo, Maik Obendorf, Muthuswamy Raveendran, Fischer OM, Oliver M. Fischer, Cemsel Bafligil, Manman Guo, R. Alan Harris, Holger Hess‐Stumpp, Alexis Laux‐Biehlmann, Alexis Laux-Biehlmann, Ernesto Lowy, Gerton Lunter, Jessica Malzahn, Nicholas G. Martin, Fernando O. Martínez, Sanjiv Manek, Manek S, Mesch S, Stefanie Mesch, Grant W. Montgomery, Montgomery GW, Andrew P. Morris, Jens Nagel, Heather A. Simmons, Denise Brocklebank, Brocklebank D, Catherine A. Shang, Susan A. Treloar, Wells G, Graham Wells, Christian M. Becker, Becker CM, Udo Oppermann, Thomas M. Zollner, Stephen Kennedy, Joseph W. Kemnitz, Jeffrey Rogers, Krina T. Zondervan
Science translational medicine · 2021 · vol. 13(608) · doi:10.1126/scitranslmed.abd6469 · PMID:34433639 · W3194699388
Other OA: closed CC0 ⤵ 22 in-corpus citations
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Neuropeptide S receptor 1 antagonism reduced peritoneal inflammation and endometriosis development in mouse models, identifying it as a potential nonhormonal therapeutic target.

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Abstract

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Receptors, G-Protein-Coupled Animals Animals Endometrium Endometrium Female Female Humans Humans Macaca mulatta Macaca mulatta Mice Mice Receptors, G-Protein-Coupled Receptors, G-Protein-Coupled Tumor Necrosis Factor-alpha

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (60)

Cited by (28)

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