Biology subjects

Ferrari, K.

Publications and source records attributed to Ferrari, K..

3 recordsLinked to original sources

bioRxiv2026

Single-Cell RNA Sequencing Reveals Commensal Microbes Amplify Sex-Specific Immune Programming in the Murine Lung

Sex-based differences in respiratory disease outcomes are well recognized. However, the underlying immunological mechanisms driving this dimorphism remain incompletely understood. While sex hormones influence immune cell development and function, the role of commensal microbes in shaping sex-specific lung immunity has not been explored. Here, we used single-cell RNA sequencing (scRNAseq) and flow cytometry to profile lung immune cells in male and female mice housed under specific pathogen-free (SPF) or germ-free (GF) conditions. Under SPF conditions, males exhibited a striking myeloid bias, with increased monocytes and macrophages, along with broad upregulation of inflammatory mediators, including S100a8, S100a9, and Il1b, across multiple cell types, and enrichment of TNF and interferon (IFN) signaling pathways. In contrast, females displayed lymphocyte-skewed profiles, with higher frequencies of T cells and natural killer (NK) cells. Interestingly, these sex-based differences in immune composition and inflammatory programs were largely absent in GF mice, indicating that microbial exposure amplifies baseline immunological dimorphism between males and females. Notably, select sex-associated features, including female-biased NK cell enrichment, persisted irrespective of microbial status, suggesting intrinsic, microbiota-independent programming. Together, these findings indicate that commensal microbes modulate sex-specific lung immunity by amplifying pre-existing intrinsic differences, highlighting the intersection of extrinsic (microbial) and intrinsic (sex-linked) factors in shaping baseline mucosal immunity.

immunology↗

bioRxiv2025

Melanocortin-responsive Kiss1 neurons of the arcuate nucleus drive energy expenditure through glutamatergic signaling to the dorsomedial hypothalamus.

Energy expenditure (EE) is essential for metabolic homeostasis, yet its central regulation remains poorly understood. Here, we identify arcuate Kiss1 neurons as key regulators of EE in male mice. Ablation of these neurons induced obesity, while their chemogenetic activation increased brown adipose tissue (BAT) thermogenesis without affecting food intake. This action is mediated by glutamatergic projections from Kiss1ARC neurons to CART/Lepr-expressing neurons in the dorsomedial hypothalamus, which activate the raphe pallidus-BAT pathway. CRISPR-mediated deletion of the vesicular glutamate transporter 2 (Vglut2) from Kiss1ARC neurons replicated the obesogenic effect. Furthermore, deletion of the melanocortin 4 receptor (MC4R) from Kiss1 neurons resulted in obesity, reduced energy expenditure and impaired thermogenesis. Optogenetic stimulation of pro-opiomelanocortin (POMC) fibers evoked inward currents in Kiss1 neurons, that were attenuated by MC4R antagonism. Our findings reveal a previously unrecognized neural circuit that mediates melanocortin action on energy expenditure, offering new insights into central mechanisms of metabolic control.

neuroscience↗

bioRxiv2024

POMC neurons control fertility through differential signaling of MC4R in Kisspeptin neurons in the female mouse

Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of MC4RKO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations; the Kiss1ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeN neurons controlling the preovulatory LH surge. Here, we show that Mc4r expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion of Mc4r in Kiss1 neurons of MC4R null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of MC4R on Kiss1ARH vs Kiss1AVPV/PeN neurons and show that MC4R activation excites Kiss1ARH neurons through direct synaptic actions. In contrast, Kiss1AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMCARH neurons acting through MC4R, directly regulate reproductive function in females by stimulating the "pulse generator" activity of Kiss1ARH neurons and restricting the activation of Kiss1AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.

neuroscience↗