Evidence map›Paper›PMID 42226209›Full record

ArticleCell communication and signaling : CCS2026

Transcriptomic profiling of the ovarian immune landscape reveals distinct macrophage subsets and activation of the NLRP3 inflammasome likely contributing to accelerated follicular atresia in classic galactosemia.

Raghuveer Kavarthapu, Son Vo, Natalie Hanby, Christophe Vanpouille, Margaret Brunette, Mary E Soliman, Thang Pham, Hong Lou, Maria DeLa Luz Sierra, Jacqueline C Yano Maher and 1 more

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Article in Cell communication and signaling : CCS, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

11 authors.

Raghuveer KavarthapuDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA. raghu.kavarthapu@nih.gov.
Son VoBioTuring Inc, San Diego, California, USA.
Natalie HanbyDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Christophe VanpouilleDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Margaret BrunetteDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Mary E SolimanDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Thang PhamBioTuring Inc, San Diego, California, USA.
Hong LouDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Maria DeLa Luz SierraDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Jacqueline C Yano MaherDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA.
Veronica Gomez-LoboDivision of Pediatric and Adolescent Gynecology; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Dr, Bldg10, Bethesda, MD, 20892, USA. veronica.gomez-lobo@nih.gov.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development 1ZIAHD008985
6 · The paper itself

Abstract

backgroundPremature ovarian insufficiency (POI) is a complication that affects 80% of females with classic galactosemia (CG), an autosomal recessive metabolic disorder caused by mutations in the GALT gene. The immune system plays a critical role in normal ovarian physiology and in the development of pathological conditions, including POI. While previous animal studies have shown that accumulation of toxic galactose metabolites trigger cellular stress pathways, and may contribute to the disease's complications, it remains unclear how these influence the ovarian immune landscape in CG patients.

methodsHere, we performed single-nucleus and spatial transcriptomic analyses on ovary biopsies from pre-pubertal girls with CG and compared with control ovary samples to explore the changes in ovarian immune milieu. We specifically investigated the gene expression profiles and altered signaling pathways in macrophages and endothelial cells. Mouse ovary cultures were treated with 50mM D-galactose for 48 h and immunohistochemical analysis was performed to evaluate the role of oxidative stress and activation of the NLRP3 inflammasome.

resultsOur transcriptomic analysis reveals diverse subpopulations of macrophages inside the ovarian stroma. We noticed a marked increase in both monocyte-derived and tissue-resident macrophages, and expression of proinflammatory cytokine genes (TNF, IL1B, CCL2, CXCL10, CXCL8) in the CG ovary. Transcriptomic profiles of endothelial cells reveal upregulation of cell-adhesion molecules (VCAM1, ICAM1, PECAM1, SELP, SELE) and chemokines (CCL21, CX3CL1) which can modulate immune cell extravasation at the site of inflammation in the CG. IHC data revealed increased expression of NLRP3, CASP-1 and TNF-α expression in the ovaries of CG. Furthermore, D-galactose toxicity in mouse ovaries resulted in oxidative stress evident by increased expression of 8-OHdG and 4-HNE, and increased atresia of ovarian follicles indicated by cleaved-CASP3 expression. We found an increased expression of NLRP3, cleaved CASP1, activated GSDMD, cleaved IL-1β and TNF-α in the D-galactose-treated mouse ovaries, suggesting inflammasome-mediated pyroptotic cell-death and inflammation, which can eventually contribute to augmented follicular atresia.

conclusionsOur findings provide molecular insights into the proinflammatory immune response driven by oxidative stress-induced activation of the NLRP3 inflammasome pathway in the CG ovary. This study elucidates the plausible role of ovarian pyroptotic macrophages in the exacerbating the inflammatory microenvironment, which may explain the early onset of POI in CG patients.

Indexed as

Follicular AtresiaGalactosemiasGene Expression ProfilingInflammasomesMacrophagesNLR Family, Pyrin Domain-Containing 3 ProteinOvaryAnimalsFemaleGalactoseHumansMiceOxidative StressGalactoseInflammasomesNLR Family, Pyrin Domain-Containing 3 Protein

Identifiers

PMID42226209
PMCPMC13439996

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.