bims-simsho 2025-09-21 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–09–21
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

Impact of sex hormones on development and progression in NEN: a new therapeutic target?
Toxicities of novel androgen receptor pathway inhibitor targeted therapies in advanced prostate cancer.
The important role of stress granules in prostate cancer development, progression, and drug resistance.
Neuroimaging-based subtypes of major depressive disorder in different sex and age groups: a potential link to sex hormone dynamics.
Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer.
Gut Microbiome and Estrogen.
Phenotypic Variations in Polycystic Ovary Syndrome: Metabolic Risks and Emerging Biomarkers.
MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.
Immunometabolic insights into women's health across all ages.
Sex differences in HIV-1 reservoir cell selection are linked to altered innate immune profiles.
Downregulated androgen receptor expression in preputial tissues of children with hypospadias.
Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 Leydig Cell Line.
Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.
Influence of biological sex on neuroinflammatory dynamics in the aging brain.
Choice of hormone assay to monitor feminizing gender-affirming hormone therapy.
S100 proteins as a key immunoregulatory mechanism for NLRP3 inflammasome.
Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells.
The potential bidirectional relationship between long COVID and menstruation.
Metabolic and Anthropometric Changes and Adverse Effects in Finnish Adolescents Using Gender-Affirming Hormonal Treatment.
Testosterone and estradiol regulate the expression of proteases and a hemoglobinase in Actinobacillus seminis.
Revealing the Complexity of Immunobiological Shifts From Non-Pregnant to Pregnant State.
Administration of levofloxacin combined with metronidazole suppositories prior to in vitro fertilisation in women with chronic endometritis: a protocol of a single-centre, randomised, controlled clinical trial.
Fibroblast growth factor 19 regulates polycystic ovary syndrome progression via FGFR4-ERK-NRF2 pathway.
Dissecting the epigenome dynamics in human immune cells upon viral and chemical exposure by multimodal single-cell profiling.
Epigenetic imprinting in innate lymphoid cell precursors directs the lineage segregation of innate lymphoid cells.
IRF8 deficiency causes anxiety-like behavior in a sex-dependent manner.

Endocr Relat Cancer. 2025 Sep 16. pii: ERC-25-0164. [Epub ahead of print]

Impact of sex hormones on development and progression in NEN: a new therapeutic target?

Roberta Modica, Alessia Liccardi, Elena Zago, Nevena Mikovic, Franz Sesti, Sofia Ballarini, Renata Simona Auriemma, Annamaria Colao.

  Neuroendocrine neoplasms (NEN) are a rare and heterogeneous group of malignancies with rising incidence, requiring multidisciplinary and personalized management. Sex is emerging as a crucial factor in NEN development and progression. Genetic, epigenetic and hormonal mechanisms have been proposed as potential contributors influencing treatment response and prognosis, but an in-depth analysis of the role of sex hormones and their receptors in NEN is still lacking. This review aims to analyze the impact of sex hormones and their receptors in sporadic NEN, to provide potential therapeutic targets in the context of precision medicine. An overview of current preclinical and clinical evidence focused on different primary NEN including gastroenteropancreatic, lung, prostate and medullary thyroid cancers, focusing on estrogen, progesterone and androgen receptors has been made to clarify their role in NEN. Variable and conflicting results emerged across different primaries. Progesterone receptors appear to play a pivotal role in pancreatic and lung NEN, while estrogen receptors are more frequently involved in small intestines NEN and medullary thyroid carcinoma, suggesting a possible role in metastatic spread. Further studies are required to increase knowledge on the underlying mechanism of sex difference in NEN, to define potential therapeutic targets for personalized care.

Keywords:  androgen receptor; estrogen receptor; neuroendocrine neoplasm; progesterone receptor; risk factor; sex difference; sex hormones

DOI:  https://doi.org/10.1530/ERC-25-0164
Curr Opin Urol. 2025 Sep 19.

Toxicities of novel androgen receptor pathway inhibitor targeted therapies in advanced prostate cancer.

Romain Iaxx, Diego Teyssonneau, Catherine Fallaha, Virginie Grouthier, Guilhem Roubaud.

   PURPOSE OF REVIEW: Advanced prostate cancer (PCa) is still dependent on the androgen receptor (AR) pathway, which has led to the development of new compounds - beyond androgen receptor pathway inhibitors (ARPIs) currently used in clinical practice - and that are able to overcome acquired resistance through AR mutations, splice variants or amplifications. With these new drugs, novel toxicities occur with new challenges for both patients and physicians. This narrative review aims to report and discuss emergent and/or related adverse events associated with these new hormonal therapies.
RECENT FINDINGS: Adrenal insufficiency-like events and cardiac disorders were the main specific adverse events associated with these new hormonal therapies for advanced PCa. Different profiles of toxicities were also related to either combination of these drugs with usual ARPIs or to compounds with multiple effects on AR pathway, mainly AR antagonism.
SUMMARY: As these new treatments are still under development, physicians need to keep up-to-date with potential emerging toxicities and manage acute and long-term toxicities.

Keywords:  androgen receptor degrader; androgen receptor ligand-binding domain mutations; androgen receptor pathway inhibitors; androgen receptor splice variants; toxicity

DOI:  https://doi.org/10.1097/MOU.0000000000001341
Gene. 2025 Sep 17. pii: S0378-1119(25)00565-7. [Epub ahead of print] 149776

The important role of stress granules in prostate cancer development, progression, and drug resistance.

Zhendong Xu, Hongjie You, Jun Gu, Junhui Jiang, Zejun Yan, Xiaofeng Jin.

  Prostate cancer (PCa) is the second most prevalent malignancy (7.3 %) and fifth leading cause of cancer death (4.1 %) in men globally. While lung cancer remains the predominant cancer in both incidence and mortality among all cancers, PCa exhibits geographically heterogeneous rising trends. Stress granules (SGs) are membraneless organelles formed through liquid-liquid phase separation (LLPS), playing a pivotal role in cellular stress responses, and are closely associated with various cancers, including PCa. Studies have shown that the expression of key SG-nucleating proteins, such as Ras-GTPase-activating protein-binding protein 1 (G3BP1), is upregulated in PCa, promoting the assembly of SGs. SGs can facilitate the initiation and progression of PCa by regulating mRNA stability, gene expression, and cellular signaling pathways, while also protecting cancer cells from damage under various stress conditions. Furthermore, SGs can modulate androgen receptor (AR) signaling, influencing PCa cell survival and sensitivity to androgen deprivation therapy (ADT). Additionally, SGs can promote PCa resistance to chemotherapy, including docetaxel (DTX), through interactions with various molecules involved in apoptosis, autophagy, and metabolism. This review summarizes the roles of SGs in the development, progression, and drug resistance of PCa, building on current advances in targeting SGs, highlights their promising potential as novel therapeutic targets for inhibiting malignant cancer progression, overcoming therapeutic resistance, and advancing PCa treatment strategies.

Keywords:  Androgen deprivation therapy; Chemotherapy resistance; G3BP1; Liquid-liquid phase separation; Oncogenesis; Prostate cancer; Stress granules

DOI:  https://doi.org/10.1016/j.gene.2025.149776
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Sep 11. pii: S0278-5846(25)00251-9. [Epub ahead of print]142 111497

Neuroimaging-based subtypes of major depressive disorder in different sex and age groups: a potential link to sex hormone dynamics.

Yuqun Zhang, Jian Ouyang, Xianhua Zhang, Ju Gao, Jialin Zhang, Yonggui Yuan.

   BACKGROUND: Functional connectivity (FC) features serve as effective biomarkers to enhance the diagnostic and treatment of major depressive disorder (MDD). While sex hormones play a crucial role in MDD pathogenesis, neuroimaging signatures specifically linked to sex hormone fluctuations remain critically underexplored for MDD identification.
METHODS: A dataset including 7316 participants with sex hormones and depression assessment was used to analyzed the relationships between depression and sex hormones across age and sex groups. Additionally, employing REST-meta-MDD dataset including 753 MDD patients, we established a novel graph classification framework based on multi-convolution network and attention pooling to identify MDD subtypes related to sex hormone dynamics RESULTS: MDD individuals of both sexes showed elevated estrogen levels than healthy controls (HC). Female MDD individuals also had higher testosterone levels than HC. Depressive symptoms differences between young and middle-aged MDD individuals were predominantly observed in females, whereas no significant age-related variations were detected in males. Our novel method achieved over 75 % accuracy in classifying young and middle-aged MDD patients. Discriminative features were mainly in the sensorimotor network for males and the cingulo-opercular network for females CONCLUSION: These findings revealed that sex- and age-specific FCs were critically in identifying MDD subtypes, especially for female patients. The indirect association with lifelong sex hormone fluctuation suggests that future research should investigate sex hormone effects across age-sex dimensions rather than merely comparing imaging differences. Thus, this approach could advance personalized MDD diagnosis and clinical interventions.

Keywords:  Depression; Functional connectivity; Sex hormone fluctuation; Subtype

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111497
Oncogene. 2025 Sep 18.

Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer.

Muj Chukhu, Ujjwal R Dahiya, Hannelore V Heemers.

The androgen receptor (AR) is a ligand-activated transcription factor that is a major driver of lethal prostate cancer (CaP) progression. Androgen deprivation therapy (ADT) that prevents the binding of androgens to AR has been the mainstay for the treatment of non-organ-confined CaP for more than 8 decades. Although ADT initially induces remissions, eventually resistance occurs while the majority of castration-resistant CaPs (CRPCs) continue to rely on AR's action for growth. Sustained AR-dependence of CaP that recurs under ADT has historically been linked to AR's transcriptional activity that controls expression of a distinct program of target genes that mediate aggressive behavior. Recently, less traditional transcriptional roles for AR, such as those impacting non-coding RNAs as well as transcription-independent roles that include AR-dependent splicing programs and translation control have been recognized to contribute to aggressive CaP features and treatment resistance. We reviewed and contrasted the contribution and relevance of these distinct functions for AR during CaP progression. We also considered the roles therein, both overlapping or mutually exclusive, for functionally diverse AR-interacting proteins that have been identified and to date have been mostly considered AR-associated transcriptional regulators. We discuss the potential implications of the involvement of AR interactors in multiple AR-dependent (non-)transcriptional cellular processes for alternative CaP treatment strategies that disrupt AR-coregulator interplay to inhibit AR-dependent transcription when AR ligand-deprivation has failed.

DOI: https://doi.org/10.1038/s41388-025-03573-z
J Menopausal Med. 2025 Aug;31(2): 95-101

Gut Microbiome and Estrogen.

Seung-Lee Park, Min-Sun Kim, Tae-Hee Kim.

  Estrogens are steroid hormones that are involved in regulating the growth, development, and functioning of the human reproductive system as well as in controlling the neuroendocrine, skeletal, adipogenesis, and cardiovascular systems. Estrogen is released into the bloodstream in two different states: as a free hormone or in association with proteins such as sex hormone-binding globulin or albumin. Unbound estrogen, which is not bound to proteins, can freely pass through cell membranes without any regulatory constraints. The microbiome is a distinct microbial population that inhabits a well-defined environment characterized by specific physio-chemical properties. It engages in a symbiotic relationship with the host, assisting in internal equilibrium regulation and immune reaction modulation. Over the years, several research investigations have underscored the importance of the microbiome in promoting wellness and preventing illnesses. An alteration in the microbiome, also known as dysbiosis, can disrupt bodily processes and contribute to the onset of ailments such as cardiovascular disorders, cancers, and respiratory conditions. The microbiome plays a crucial role in maintaining human health. Several elements affect the balance of the intestinal microecological system such as dietary habits, medication usage, pathogens, and endocrine factors. Recent research has indicated a disparity between genders in the prevalence of certain diseases associated with the microbiome, with sex hormones playing a crucial role in affecting specific health conditions.

Keywords:  Dysbiosis; Estrogens; Microbiome; Microbiota

DOI:  https://doi.org/10.6118/jmm.24024
J Endocrinol. 2025 Sep 19. pii: JOE-25-0226. [Epub ahead of print]

Phenotypic Variations in Polycystic Ovary Syndrome: Metabolic Risks and Emerging Biomarkers.

Yi-Cih Ma, Kim-Seng Law, Wen-Sheng Wang, Hsun-Ming Chang.

  Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with diverse clinical manifestations and metabolic risks. The 2012 NIH phenotypic classification, based on the presence of hyperandrogenism (HA), ovulatory dysfunction (OD), and polycystic ovarian morphology (PCOM), has enabled more nuanced characterization of PCOS into four phenotypes (A-D). Phenotypes A and B, both hyperandrogenic and anovulatory, are consistently associated with the highest metabolic risk, including insulin resistance, dyslipidemia, and increased prevalence of metabolic syndrome. Phenotype C, though ovulatory, still exhibits metabolic abnormalities due to androgen excess. In contrast, phenotype D, lacking hyperandrogenism, generally shows the mildest hormonal and metabolic profiles. This review outlines the evolving diagnostic landscape of PCOS, including the potential use of Anti-Müllerian hormone (AMH) as a surrogate marker for PCOM. It explores hormonal and metabolic biomarkers, such as total and free testosterone, SHBG, LH/FSH ratio, HOMA-IR, and lipid parameters, in phenotype differentiation. Furthermore, emerging adipokines (e.g., adiponectin, chemerin, ZAG) and inflammatory markers (e.g., CRP, IL-6, TNF-α) provide additional insight into the metabolic heterogeneity of PCOS beyond obesity. Genetic and genomic studies have identified over 19 susceptibility loci involved in gonadotropin regulation, steroidogenesis, and insulin signaling, with distinct gene clusters aligning with adiposity, insulin resistance, and reproductive traits. MicroRNA signatures also show potential as phenotype-specific biomarkers. Recognizing phenotype-specific variations in PCOS is critical for individualized risk assessment and therapeutic strategies. Future research should prioritize standardized diagnostic criteria and large, diverse cohorts to validate emerging biomarkers and improve long-term outcomes for women with PCOS.

Keywords:  PCOS diagnosis; PCOS phenotypes; biomarkers; metabolic risk; polycystic ovarian syndrome

DOI:  https://doi.org/10.1530/JOE-25-0226
Prostate. 2025 Sep 19.

MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.

Changying Li, Chenchen He, Jiancheng Pan, Yuhong Feng, Dawei Tian, Jinhuan Meng, Zhi Qi, Changlin Li, Kuo Yang.

   OBJECTIVE: Androgen deprivation therapy (ADT) was the frontline treatment for patients with prostate cancer ineligible for radical prostatectomy. However, the development of resistance to ADT significantly limits its clinical efficacy.
METHODS: Using a genome-wide CRISPR/Cas9 knockout (GeCKO) library screen combined with single-cell RNA sequencing (scRNA-seq) analysis, we identified key genes involved in ADT resistance.
RESULTS: Macrophage migration inhibitory factor (MIF) was identified as a critical mediator of ADT resistance. Inhibition of MIF significantly overcomes ADT resistance. Moreover, we found that the androgen receptor (AR), but not its splice variant AR-V7, negatively regulates MIF expression. Consequently, inhibition of the AR signaling pathway via ADT results in the upregulation of MIF expression. Elevated expression of MIF promotes prostate cancer cell proliferation by upregulating AMPD2 expression.
CONCLUSIONS: Our findings demonstrate that ADT induces MIF upregulation, which in turn drives prostate cancer cell proliferation via upregulating AMPD2 expression, eventually contributing to the development of resistance to ADT.

Keywords:  MIF; androgen deprivation therapy; prostate cancer; purine metabolism; resistance

DOI:  https://doi.org/10.1002/pros.70053
Maturitas. 2025 Sep 09. pii: S0378-5122(25)00527-4. [Epub ahead of print]202 108719

Immunometabolic insights into women's health across all ages.

Marta Matos-Silva, Fábio Santos Lira, Barbara Moura Antunes.

  The reproductive phase in women is characterized by fluctuations in sex hormones, as observed during the menstrual cycle. With aging, hormonal transitions occur, leading to a decline in sex hormones and the onset of menopause. These hormonal fluctuations throughout a woman's life significantly impact immune cell activity and metabolism. This literature review elucidates the effects of female sex hormones, particularly estradiol, on immunometabolic modulation in adult and elderly women. Additionally, the review explores the impact of physical activity and exercise as strategies for modulating inflammation, metabolic changes, and preventing chronic non-communicable diseases (CNCDs). The findings indicate that during the menstrual cycle, sex hormones are significantly associated with inflammatory and lipid proteins, particularly pro-inflammatory markers (such as TNF-α, IL-1β, IL-6), LDL-c and non-HDL in the luteal phase, and influence the distribution of specific immune cells (such as monocytes and neutrophils). With the decline in sex hormone concentrations, evidence suggests that women experience a pronounced inflammatory profile, marked by significant secretion of pro-inflammatory cytokines due to a shift in immune cell phenotype, reinforcing the relationship between sex hormones and the inflammatory response. However, the literature is beginning to demonstrate more consistently the beneficial effects of exercise training, as it promotes the release of anti-inflammatory and protective markers (such as IL-10, IL-6, HDL-c, HDL/LDL ratio) through improvements in the cellular profile, directly contributing to an enhancement of the immunometabolic profile and the prevention of chronic diseases.

Keywords:  Aging; Cytokines; Exercise training; Hormonal transition; Inflammation; Menstrual cycle

DOI:  https://doi.org/10.1016/j.maturitas.2025.108719
Sci Transl Med. 2025 Sep 17. 17(816): eadu7154

Sex differences in HIV-1 reservoir cell selection are linked to altered innate immune profiles.

Toong Seng Tan, Ce Gao, Alexander S Hochroth, Liliana Vela, Leah Carrere, Sruthi Kalavacherla, Seohyun Hong, Melanie Lancien, Chloe M Naasz, Aischa Niesar, Samantha K Marzi, Isabelle C Roseto, Benjamin Bone, Xiaodong Lian, Yuko Yuki, Mathias Viard, Rebecca Hoh, Deborah K McMahon, Ronald J Bosch, Seble G Kassaye, Rajesh T Gandhi, Mary Carrington, Steven G Deeks, Phyllis C Tien, Michael J Peluso, Jeffrey M Jacobson, Mathias Lichterfeld, Xu G Yu.

HIV-1 persistence despite suppressive antiretroviral therapy (ART) is primarily because of infected memory CD4 T cells, so-called viral reservoir cells, that harbor chromosomally integrated viral DNA as a "provirus" and resist clearance by the human immune system. Biological sex affects host immune responses and may influence selection and evolution of HIV-1 reservoir cells during long-term ART for HIV infection. We assessed more than 4073 individual proviruses through single-molecule amplification from 30 females and 35 males living with HIV-1 and treated with ART for a median of 20 years. We observed that the HIV-1 reservoir profile in females was characterized by lower proviral phylogenetic complexity, an increased proportion of clonally expanded intact proviruses, and a higher proportion of intact proviruses integrated into repressive heterochromatin locations of the human genome. The evolution of this distinct viral reservoir profile in females was associated with an improved signature of innate immune responses, specifically those of NK cells. On the contrary, signs of viral sequence adaptation to adaptive T cell immune responses were more pronounced in intact HIV-1 proviruses from males. Collectively, these data suggest a stronger ability of the female immune system to drive immune selection of HIV-1 reservoir cells during ART, putatively because of improved innate immune function.

DOI: https://doi.org/10.1126/scitranslmed.adu7154
Front Pediatr. 2025 ;13 1660777

Downregulated androgen receptor expression in preputial tissues of children with hypospadias.

Zhilin Yang, Peiliang Zhang, Tiejun Zhang, Jianchun Yin, Guanglun Zhou, Weiguang Zhao, Pengyu Chen, Jiaqiang Li, Shoulin Li.

   Purpose: To resolve conflicting evidence on androgen receptor (AR) expression in hypospadias, we compared preputial AR levels between affected children and controls.
Methods: Forty patients with isolated hypospadias (age 2.9 ± 0.79 years, range 1.6-5.2 years) and 40 normal boys (age 3.2 ± 0.79 years, range 1.8-4.7 years) who underwent circumcision for phimosis were included in our study. Inner plates of preputial tissues were analyzed by immunohistochemistry for AR detection.
Results: AR immunoreactivity was predominantly localized to the basal epithelial layer. Significantly reduced AR expression was observed in hypospadias patients vs. controls [average optical density (AOD), 0.38 ± 0.09 vs. 0.56 ± 0.11]. However, there was no difference in AR expression between the proximal and distal hypospadias (AOD, 0.40 ± 0.07 vs. 0.37 ± 0.10, P = 0.22).
Conclusions: Preputial AR downregulation in hypospadias implicates AR deficiency in pathogenesis, providing evidence to resolve a key controversy in the field.

Keywords:  androgen receptor; children; expression; hypospadias; prepuce

DOI:  https://doi.org/10.3389/fped.2025.1660777
Mol Cell Endocrinol. 2025 Sep 12. pii: S0303-7207(25)00209-6. [Epub ahead of print] 112658

Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 Leydig Cell Line.

Aikaterini Kallianioti, Guillaume Bourdon, Claire Chevaleyre, Christine Péchoux, Christelle Ramé, Jérôme Bourgeais, Olivier Hérault, Nancy Geoffre, Thomas Darde, Ingrid Plotton, Véronique Douard, Joëlle Dupont, Pascal Froment.

  Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown. GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the Glut5 gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach. Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as Hsd3b and steroidogenic acute regulatory protein (StAR). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as Akap5, Slc39a9, an androgen receptor or lactate dehydrogenase A (Ldha), which produces lactate, and downregulation of several genes associated with the insulin pathway such as Tsc2 or the hexokinase Hkdc1. In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of sperm production and quality, as well as sexual behavior, as described in the GLUT5 KO mouse model.

Keywords:  Fructose; GLUT5; Leydig cell line; Omics; Testosterone

DOI:  https://doi.org/10.1016/j.mce.2025.112658
EMBO J. 2025 Sep 16.

Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.

Yi-Hao Wang, Limei Wang, Ping-Chih Ho.

  Cellular metabolism plays a pivotal role in regulating the effector functions and fate decisions of immune cells, shaping immune responses in homeostasis and disease. Metabolic pathways also serve as critical signaling hubs governing immune cell behavior. Deregulated metabolic pathways contribute to immune dysfunction, fueling disease progression and creating challenges for therapeutic interventions. The recent development of advanced technologies to delineate immunometabolic regulation has revolutionized our understanding of immune cell biology. These tools, ranging from quantitative single-cell metabolomics to in vivo spatial tissue profiling and DC-based metabolic therapy, have shifted the focus from broad nutrient pathways to a detailed exploration of metabolic reprogramming within disease microenvironments, revealing how metabolic changes drive immune cell activation, differentiation, and effector responses. The integration of immunometabolic insights into clinical practice holds strong potential for advancing precision medicine and developing targeted therapies that restore immune balance in pathological conditions. Here, we summarize emerging cutting-edge technologies related to immunometabolism and critically reflect on their current limitations. Finally, we discuss potential needs for developing novel methods that can uncover the intricate interplay between metabolism and immune cell function.

Keywords:  Dendritic Cells; Immunometabolism; Metabolic Reprogramming; T Cells; Technological Advances

DOI:  https://doi.org/10.1038/s44318-025-00569-z
Front Aging Neurosci. 2025 ;17 1670175

Influence of biological sex on neuroinflammatory dynamics in the aging brain.

Ludmila Müller, Svetlana Di Benedetto, Viktor Müller.

  The aging brain undergoes complex neuroinflammatory changes that are increasingly recognized as contributing factors to the development and progression of neurodegenerative diseases. Emerging research reveals that biological sex profoundly shapes these neuroinflammatory dynamics, resulting in distinct trajectories of immune function, glial activity, and neural vulnerability in males and females. This mini-review focuses on recent advances in understanding the interplay of hormonal, genetic, and epigenetic factors that drive sex-specific differences of neuroinflammatory processes in aging brain. We begin by describing the hallmarks of neuroinflammation, including chronic activation of glial cells and the loss of inflammatory resolution. We provide a brief overview of age-related changes in microglial and astrocyte function, along with systemic influences such as immunosenescence, inflammaging, dysbiosis, and increased blood-brain barrier permeability. Building on this foundation, we examine sex-dependent differences in immune aging, CNS immune surveillance, and hormonal regulation of glial activity, particularly in the context of menopause and andropause. Particular attention is given to how these mechanisms drive sex-specific differences in the pathophysiology of neuroinflammation-a key contributor to many neurodegenerative diseases. Finally, we address key methodological challenges-such as the underrepresentation of females in preclinical models and limited sex-stratified clinical analyses-that constrain our understanding of sex-specific neuroinflammation in aging. By integrating sex as a critical biological variable and exploring systems-based approaches such as multilayer network models, this review highlights the importance of sex-informed research to better understand, prevent, and treat neuroinflammatory and neurodegenerative conditions in aging populations.

Keywords:  aging brain; cytokines; glial cells; immune cells; immunosenescence; neurodegenerative diseases; neuroinflammation; neurons

DOI:  https://doi.org/10.3389/fnagi.2025.1670175
Endocr Pract. 2025 Sep 11. pii: S1530-891X(25)01020-1. [Epub ahead of print]

Choice of hormone assay to monitor feminizing gender-affirming hormone therapy.

Daniel J Slack, Nithya Krishnamurthy, Meghan Garrity, Derek Chen, Moira Kyweluk, Eli Trakhtenberg, Jerrica Kirkley, Joshua D Safer.

   CONTEXT: Studies have shown variability in the correlation among testosterone (T) concentrations, estradiol (E2) concentrations, and other clinical parameters to monitor response to feminizing gender-affirming hormone therapy (GAHT). We aimed to determine the degree to which data support the use of serum T, serum E2, luteinizing hormone (LH), or follicle stimulating hormone (FSH) to monitor feminizing GAHT with the goal of decreasing the effect of endogenous androgens.
METHODS: We conducted a cross-sectional analysis of T and E2 concentrations in 9,916 transfeminine individuals prescribed estradiol to examine the association between individuals' most recent serum T, E2, LH and FSH concentrations in the context of feminizing GAHT treatment.
RESULTS: Changes in T concentrations were inversely correlated with changes in E2 concentrations (p<.001). However, orchiectomy, age, and the use of spironolactone were associated with changes in T, but not E2 concentrations (p<.001). Changes in T concentrations were also correlated with changes in LH (p<.05). Such correlations were not demonstrated with E2 concentrations.
CONCLUSIONS: To monitor feminizing GAHT, it may be reasonable to favor target T concentrations over E2 concentrations in patients with testes and to consider LH concentrations in patients without testes who are not taking GnRH agonists.

Keywords:  LH; estradiol; orchiectomy; spironolactone; testosterone; transgender

DOI:  https://doi.org/10.1016/j.eprac.2025.08.010
Front Immunol. 2025 ;16 1663547

S100 proteins as a key immunoregulatory mechanism for NLRP3 inflammasome.

Shahinur Acter, Qing Lin.

  The S100 superfamily of proteins consists of Ca2+-binding proteins characterized by the EF-hand motif. Certain members of this protein family, such as S100A8, S100A9, and S100A12, have been effectively utilized as biomarkers for the detection and evaluation of prognosis in immunological diseases. These proteins are also identified as damage-associated molecular pattern (DAMP) molecules, which exhibit significant upregulation in various autoimmune disorders, cancers, and neurodegenerative diseases. Following tissue injury, necrotic or immune cells release or secrete DAMPs to initiate inflammatory responses. This signaling further creates autocrine and paracrine positive feedback loops that amplify and sustain the inflammatory response. The NLRP3 inflammasome pathway is a pivotal component in these DAMP-induced immune regulatory mechanisms. This review summarizes the regulatory roles of S100 protein family in NLRP3 inflammasome signaling and their functions in innate and adaptive immunity, with an emphasis on pulmonary hypertension. Moreover, we examine the interactive feedback mechanisms among NLRP3 inflammasome, S100A8/A9, and Gasdermin D, exploring their implications in autoimmune diseases.

Keywords:  DAMP; S100A8; S100A9; gasdermin D; inflammasome; pulmonary hypertension

DOI:  https://doi.org/10.3389/fimmu.2025.1663547
Am J Reprod Immunol. 2025 Sep;94(3): e70168

Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells.

Takashi Matsuzaki, Hiroaki Hamaguchi, Ken R Ito, Ryota Nakagawa, Hiroya Nakamura, Hiroaki Ito, Chiyuki Ueshima, Akihiko Yoshizawa, Hironori Haga, Tatsuki R Kataoka.

   PROBLEM: Gonadotropin-releasing hormone (GnRH), primarily known for its hypothalamic role in regulating gonadotropin secretion, is also expressed in extra-hypothalamic tissues, including trophoblasts at implantation sites. We investigated the association between trophoblasts and mast cells, demonstrating their role in producing leukemia inhibitory factor (LIF) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesized an additional interaction between trophoblasts and mast cells mediated by GnRH.
METHOD OF STUDY: Immunohistochemical analysis was conducted to investigate GnRH receptor (GnRHR) expressing mast cell in endometrial and tubal tissues from both pregnant and non-pregnant conditions (2005-2018). We established a human mast cell line LAD2 with forced expression of GnRHR expression (GnRHR-expressing LAD2) via lentiviral transfection method. The cells were stimulated with or without leuprorelin (1 µM) and transcriptomic analysis and cell migration assays were conducted.
RESULTS: GnRHR is expressed in decidual mast cells during uterine pregnancy and in mast cells adjacent to or embedded in trophoblasts of tubal pregnancy. Notably, GnRHR expression was also observed in endometrial mast cells in non-pregnancy conditions. The levels of transcripts encoding LIF, MMP-9, and a natural killer (NK) cell attractant C-X-C motif chemokine ligand 16 (CXCL16) were significantly upregulated in GnRHR-expressing LAD2 than in control cells. In addition, culture supernatants from GnRHR-expressing LAD2 cells enhanced the migration of the trophoblast cell line HTR-8/SVneo and the NK cell line NK-92 MI.
CONCLUSIONS: These findings suggest that GnRHR expression in mast cells promotes their supportive role in pregnancy establishment by increasing the LIF, MMP-9, and CXCL16 productions, recruiting trophoblasts and NK cells.

Keywords:  CXCL16; GnRH; GnRH receptor; LIF; MMP9; mast cell; pregnancy

DOI:  https://doi.org/10.1111/aji.70168
Nat Commun. 2025 Sep 16. 16(1): 8187

The potential bidirectional relationship between long COVID and menstruation.

Jacqueline A Maybin, Catherine Walker, Marianne Watters, Natalie Zm Homer, Joanna P Simpson, Cara Robb, Douglas A Gibson, Luna Jeanjean, Hilary O D Critchley, Gabriella Kountourides, Zuzanna Olszewska, Alexandra Alvergne.

Women have reported menstrual changes following SARS-CoV-2 infection and variation in long COVID symptoms across the menstrual cycle. We examined (i) whether COVID is linked to abnormal uterine bleeding (AUB), (ii) if long COVID symptoms vary with the menstrual cycle, and (iii) potential underlying mechanisms. Here we show long COVID was associated with AUB in a UK population. When compared to those never infected (n = 9423), long COVID participants (n = 1048) reported increased menstrual volume, duration and intermenstrual bleeding, while those who recovered from acute COVID (n = 1,716) reported minimal menstrual disruption. Long COVID symptoms examined in 54 women across the menstrual cycle revealed that severity was highest during the perimenstrual and proliferative phases. Serum and endometrial analysis revealed higher serum 5α-dihydrotestosterone and lower endometrial androgen receptors in long COVID versus no COVID. Other ovarian hormones showed no significant differences. Serum cytokine profiling indicated increased menstrual inflammation with long COVID and immune cell aggregates were observed in menstrual endometrium. In conclusion, long COVID was associated with AUB but not impaired ovarian function. Differences in peripheral and endometrial inflammation may contribute to AUB and long COVID symptom severity. We anticipate our findings will instigate exploration of new therapeutic strategies for women with long COVID.

DOI: https://doi.org/10.1038/s41467-025-62965-7
Transgend Health. 2025 Sep;10(4): 306-315

Metabolic and Anthropometric Changes and Adverse Effects in Finnish Adolescents Using Gender-Affirming Hormonal Treatment.

Nico Vehmas, Elina Holopainen, Hanna Savolainen-Peltonen.

   Purpose: In this retrospective study our purpose was to assess whether hormone interventions for gender dysphoria pose additional somatic risks for adolescents. We examined changes in metabolic laboratory parameters, body mass index (BMI), and blood pressure (BP) and analyzed adverse effects during gender-affirming hormonal treatment (GAHT).
Methods: We analyzed follow-up data on 119 transgender adolescents using GAHT at the adolescent gynecology clinic in Helsinki University Hospital, Finland from January 2010 to January 2022.
Results: During the study period, 99 (83%) transgender males and 20 (17%) transgender females started GAHT. The median GAHT follow-up duration was 34.0 (interquartile range 17.2) months. Mean hemoglobin (HB) and hematocrit (HCT) levels increased by 16% (p < 0.001) during testosterone treatment, decreased by 10% (p < 0.01) during estrogen treatment, and plateaued after one year. During the initial follow-up, no clinically relevant changes were seen in glucose and lipid metabolism, BMI, or BP. Adverse effects leading to testosterone dose reduction were reported in 19% of transgender males and were less common when gonadotropin-releasing hormone analog was used in testosterone treatment initiation (11.1% vs. 27.8%, p = 0.04). Somatic adverse effects requiring hospitalization or permanent discontinuation of GAHT were not reported.
Conclusion: The somatic changes observed in this study were typical for GAHT. No serious somatic adverse effects occurred. Regular measuring of HB and HCT in transgender males undergoing GAHT is warranted, but excessive monitoring of glucose and lipid metabolism, BMI, and BP during the initial follow-up period may not be necessary for somatically healthy adolescents.

Keywords:  adolescents; gender dysphoria; gender-affirming hormonal treatment; hematocrit; metabolism

DOI:  https://doi.org/10.1089/trgh.2024.0012
FEMS Microbiol Lett. 2025 Sep 18. pii: fnaf097. [Epub ahead of print]

Testosterone and estradiol regulate the expression of proteases and a hemoglobinase in Actinobacillus seminis.

Gerardo A Ramírez-Paz-Y-Puente, José A Gutiérrez-Pabello, Edgar Zenteno, Tomás E Villamar-Duque, Erika P Meneses-Romero, Candelario Vazquez-Cruz, Erasmo Negrete-Abascal.

  Actinobacillus seminis is a causative agent of epididymitis, infertility, and sterility in sexually mature ruminants. Previous studies suggest that sex hormones regulate the expression of A. seminis virulence factors, promote its growth, and support adhesin expression and biofilm formation; however, the effects of these hormones on protease expression are unknown. The effects of testosterone (1-5 ng/ml) and estradiol (5-25 pg/ml) were evaluated on the A. seminis protease expression. Zymograms revealed that both hormones enhanced the secretion of a 50 kDa metalloprotease and a 65 kDa serine protease. The 65 kDa serine protease showed optimal activity at a pH of 6-8, was stable at temperatures up to 70°C, and hydrolyzed bovine hemoglobin and casein; interestingly, this hemoglobin protease was expressed after treatment with sex steroid hormones but not in the presence of catecholamines. This serine-protease presents identity with two A. seminis serine proteases of 50 kDa. The metalloprotease has previously been shown to hydrolyze bovine IgG and fibrinogen and presented identity with a carboxy-terminal protease. Both proteases showed immune cross-reactivity with hyperimmune sera against metalloproteases from A. seminis and A. pleuropneumoniae, and with serum against a Mannheimia haemolytica serine protease. Our results suggest that hormones affect the expression of different A. seminis virulence factors, such as proteases, and may play a key role in bacterial pathogenesis.

Keywords:   Actinobacillus seminis ; casein; estradiol; hemoglobin; protease; testosterone

DOI:  https://doi.org/10.1093/femsle/fnaf097
Am J Reprod Immunol. 2025 Sep;94(3): e70166

Revealing the Complexity of Immunobiological Shifts From Non-Pregnant to Pregnant State.

Chelsea A DeBolt, Haocheng Yu, Valerie Riis, Liqhwa Ncube, Amir Horowitz, Michal A Elovitz.

   PROBLEM: Significant immunological shifts, systemically and at the maternal-fetal interface, are required for successful pregnancy. As immune perturbations are emerging as pivotal drivers of adverse maternal health, elucidating how normal pregnancy alters maternal systemic immunity is imperative.
METHODS: From our prospectively enrolled cohort of Black women, peripheral blood samples were collected pre-pregnancy (V1) and in the second trimester (16-24 weeks, V2). Among those who became pregnant, 23 had available samples from both time points. RNA was extracted and subjected to bulk RNA sequencing, followed by differential gene expression analyses, immune cell-type deconvolution, and pathway enrichment analyses. Participants were stratified by pre-pregnancy obesity (body mass index ≥ 30 kg/m2) to examine its impact on pregnancy-induced immune changes.
RESULTS: Pathway analyses revealed innate immune activation and increased neutrophil-driven inflammation during pregnancy. Significant increase in neutrophils and monocytes occurred during pregnancy, whereas naïve CD8+ T-cell and B-cell subsets were significantly decreased. Pre-pregnancy obesity amplified these changes, further increasing innate populations (gamma delta T cells, neutrophils) and decreasing adaptive populations (CD8 naïve T cells, B memory cells).
CONCLUSION: From individuals with uncomplicated pregnancies, we demonstrate dramatic immunological changes when transitioning from a non-pregnant to pregnant state. Intricate immune modulation, including changes in inflammatory mechanisms and immune cell dynamics were observed. Pre-pregnancy obesity enhances these inflammatory shifts, providing insights into potential mechanisms driving adverse pregnancy outcomes in obese women. Future studies investigating how these immunological shifts are required for optimal maternal health and/or may promote increased vulnerability to adverse pregnancy outcomes will create new opportunities to improve maternal outcomes.

Keywords:  immune system; inflammation; maternal; neutrophil; obesity; pregnancy

DOI:  https://doi.org/10.1111/aji.70166
BMJ Open. 2025 Sep 15. 15(9): e098500

Administration of levofloxacin combined with metronidazole suppositories prior to in vitro fertilisation in women with chronic endometritis: a protocol of a single-centre, randomised, controlled clinical trial.

Mingmei Lin, Yue Wang, Xiaodong Lv, Zeyang Lin, Zhonghong Zeng, Dan Mo, Hongying Shan, Rong Li.

   INTRODUCTION: Chronic endometritis (CE) is regarded as a potential factor contributing to infertility and embryo implantation failure. The cause of CE remains unclear at present, but it might be associated with intrauterine microbial infections. Empirical antibiotic treatment typically consists of a 2-week course of oral levofloxacin combined with oral metronidazole. Currently, there is no research comparing the efficacy of oral levofloxacin versus vaginal metronidazole suppositories in improving pregnancy outcomes for these patients. This study aims to evaluate the effectiveness of combining oral levofloxacin with metronidazole suppositories in the treatment of CE. The goal is to enhance clinical pregnancy rates and live birth rates among patients undergoing in vitro fertilisation (IVF), while concurrently mitigating the incidence of miscarriages.
METHODS AND ANALYSIS: The trial concerning the combination of levofloxacin and metronidazole suppositories for the treatment of CE is a single-centre, randomised controlled clinical trial. We plan to recruit female patients with CE who are planning to undergo IVF. Following informed consent, eligible participants will be randomly assigned in a 1:1 ratio to receive either daily oral levofloxacin combined with oral metronidazole or oral levofloxacin combined with a metronidazole suppository for 2 weeks until the human chorionic gonadotropin trigger day. All IVF procedures will be carried out routinely at this centre. The primary outcome is the live birth rate after embryo transfer, while the secondary pregnancy outcomes include clinical pregnancy rates and miscarriage rates.
ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Peking University Third Hospital on 28 June 2024 (Reference No. IRB00006761-M2023857). Written informed consent will be acquired from all participants prior to randomisation. The study findings will be submitted to scientific conferences and peer-reviewed journals.
TRIAL REGISTRATION NUMBER: NCT06650540.

Keywords:  Inflammation; Medicine; Pregnancy

DOI:  https://doi.org/10.1136/bmjopen-2024-098500
Front Cell Dev Biol. 2025 ;13 1626938

Fibroblast growth factor 19 regulates polycystic ovary syndrome progression via FGFR4-ERK-NRF2 pathway.

Junjie Qu, Meiting Qiu, Jingyun Wang, Zhiqin Chen, Miaoxin Chen, Xiaoming Teng, Yiran Li.

   Background: FGF19, an endocrine hormone, participating in ovarian function. This study investigated the roles of FGF19 in polycystic ovary syndrome (PCOS) and its associated molecular mechanisms, specifically focusing on the FGFR4-ERK-NRF2 pathway.
Methods: Clinical samples were collected to determine FGF19 levels, and proteomic analysis was performed on follicular fluid. A mouse model was established to investigate the molecular pathogenesis of PCOS. Subsequently, a series of in vitro experiments explored the effects and mechanisms of FGF19 on PCOS with and without oxidative stress.
Results: Proteomics identified 144 differentially expressed proteins enriched in pathways including VEGF, PPAR, IL-2-STAT5, mTORC1, epithelial-mesenchymal transition, bile acid metabolism, and oxidative phosphorylation. FGF19/FGF15 levels were significantly higher in PCOS patients and mice compared to controls. In PCOS mice, FGFR4, NRF2, and HO1 were upregulated, while p-ERK/ERK levels were decreased. FGF19 overexpression promoted KGN cells viability while inhibiting apoptosis, upregulating FGFR4, NRF2, HO1, BCL2, and p-ERK/ERK, and downregulating BAX. However, LY3214996 reversed the action of FGF19 overexpression in KGN cells. H2O2 treatment decreased KGN cell viability, increased apoptosis, and elevated ROS levels. NRF2 knockdown further aggravated H2O2's effectd, whereas FGF19 overexpression countered the changes in viability, apoptosis, and ROS levels caused by H2O2. Furthermore, H2O2 stimulation upregulated BAX, NRF2, and HO1, while decreasing BCL2 and p-ERK/ERK levels; NRF2 knockdown further upregulated BAX and downregulated BCL2 and p-ERK/ERK. Conversely, FGF19 overexpression had opposite effects on NRF2 knockdown.
Conclusion: FGF19 may be involved in PCOS occurrence and development through the regulation of the FGFR4-ERK-NRF2 pathway.

Keywords:  ERK pathway; FGF19; Nrf2; oxidative stress; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fcell.2025.1626938
bioRxiv. 2025 Sep 09. pii: 2025.09.09.675101. [Epub ahead of print]

Dissecting the epigenome dynamics in human immune cells upon viral and chemical exposure by multimodal single-cell profiling.

Irem B Gündüz, Bei Wei, Derek C Chen, Wenliang Wang, Manoj Hariharan, Todd Norell, Timothy J Broderick, Micah T McClain, Lisa L Satterwhite, Thomas W Burke, Elizabeth A Petzold, Xiling Shen, Christopher W Woods, Vance G Fowler, Felicia Ruffin, Parinya Panuwet, Dana B Barr, Aaron J Wilk, Madeline J Lee, Catherine Blish, Flora Castellino, Anna Maria Walley, Thomas Evans, Joseph R Ecker, Fabian Müller, William J Greenleaf.

Pathogen and chemical exposures lead to profound remodeling of the gene-regulatory landscape across human immune cell populations. Here, we present a single-nucleus chromatin accessibility atlas of human immune cells of individuals exposed to HIV-1, COVID-19, Influenza virus, organophosphates as well as healthy controls that provides insights into gene regulation driven by these cell-extrinsic stimuli. This atlas comprises 271,299 cells and 319,420 candidate regulatory elements that exhibit dynamic accessibility associated with gene expression across immune cell states. Our longitudinal HIV cohort reveals epigenetic signatures of T cell exhaustion, manifested in changes in the accessibility of binding sites for the FOXP family transcription factors. We further identified changes in the accessibility of candidate regulatory elements in CD14 monocytes upon SARS-CoV-2 exposure that are associated with a switch in NF-κB to AP-1-based regulation of cytokine networks. By integrating single-cell profiles of DNA methylation from matched samples we created a multimodal epigenome atlas of human immune cells across exposure states using the accessibility-derived candidate regulatory elements. Both modalities exhibit complementary epigenetic signatures at transcription factor binding sites associated with cell state, as exemplified in the process of memory formation in T-cells. Finally, by linking potentially regulatory DNA methylation signatures to changes in chromatin accessibility in monocytes, we identify AP1 motifs exhibiting epigenetic dynamics, indicating selective remodeling in TF networks in severe cases of COVID-19.

DOI: https://doi.org/10.1101/2025.09.09.675101
Nat Immunol. 2025 Sep 18.

Epigenetic imprinting in innate lymphoid cell precursors directs the lineage segregation of innate lymphoid cells.

Zhen Liu, Fei Shao, Qiang Zhang, Min Zhao, Shuai Gao, Xusheng Zhang, Dou Yu, Jingyao Zhang, Pengyan Xia, Shuo Wang.

Innate lymphoid cells (ILCs) are essential for mucosal homeostasis, but the epigenetic regulation of their lineage segregation remains elusive. Here we simultaneously profiled the single-cell DNA methylome, chromatin accessibility and transcriptome of ILC subsets and ILC precursors (ILCPs) and found that ILCPs could be divided into two subgroups (ILCP1 and ILCP2). ILCP2s had highly heterogeneous DNA methylation profiles and could be divided into three groups according to their DNA methylation characteristics, which matched those of ILC subsets. We identified the signature methylation regions (SMRs) of each ILC subset and traced the DNA methylation imprinting during ILCP differentiation. ILCP2s with hypomethylated SMRs characteristic of ILC subsets differentiated into those subsets. DNA methylation editing of SMRs suppressed ILC lineage segregation, while deletion of Dnmt1 in ILCPs abrogated the heterogeneous distribution of SMRs and resulted in ILC differentiation defects. These findings provide evidence that epigenetic imprinting determines lineage segregation during immune cell development.

DOI: https://doi.org/10.1038/s41590-025-02261-0
bioRxiv. 2025 Sep 04. pii: 2025.09.02.673764. [Epub ahead of print]

IRF8 deficiency causes anxiety-like behavior in a sex-dependent manner.

Stella Zhu, Keita Saeki, Rose-Marie Karlsson, Daniel Abebe, Keiko Ozato.

Anxiety disorder is a serious psychiatric disease that affects women twice more than men and disrupts patients' daily lives. It is often comorbid with major depression and other mental diseases. Various underlying mechanisms have been proposed, such as neurotransmitters and neuroanatomical disruptions, and more recently, oxidative stress; however, much remained unclear, including the role of glial cells. Here, we investigated the role of IRF8 in anxiety disorders in the mouse model. IRF8 is a transcription factor expressed primarily in microglia in the brain. A battery of behavioral tests revealed that female IRF8 knockout (IRF8KO) mice show increased anxiety relative to male IRF8KO and wild-type mice. Female IRF8KO mice also exhibited a higher tendency for obsessive-compulsive disorder. However, these behavioral abnormalities were not observed when IRF8 was deleted postnatally, indicating that it acts during the fetal stage to control anxiety. Transcriptome analysis revealed that IRF8 deficiency leads to redox dysregulation. Further, 2',7'-dichlorofluorescin diacetate (DCFDA) staining for microglia demonstrated that female IRF8KO microglia produce higher levels of reactive oxygen species (ROS) compared to WT and male IRF8KO counterparts. Detailed RNA-seq analysis, however, did not reveal specific genes that cause high ROS production in female cells. In sum, this work demonstrates that IRF8 in microglia plays a major role in controlling anxiety in a sex dependent manner.

DOI: https://doi.org/10.1101/2025.09.02.673764