Unravelling the sex-specific diversity and functions of adrenal gland macrophages

Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression. In adulthood, monocyte recruitment dominates adrenal gland macrophage maintenance in female mice. Adrenal gland macrophage sub-tissular distribution follows a sex-dimorphic pattern, with MHC class IIlow macrophages located at the cortico-medullary junction. Macrophage sex dimorphism depends on the presence of the cortical X-zone. Adrenal gland macrophage depletion results in altered tissue homeostasis, modulated lipid metabolism, and decreased local aldosterone production during stress exposure. Overall, these data reveal the heterogeneity of adrenal gland macrophages and point toward sex-restricted distribution and functions of these cells.</p

Phenotypic and functional analysis of sexual dimorphism in adrenal gland macrophages

Les macrophages sont des cellules immunitaires innées retrouvées dans tous les tissus et constituent la première ligne de défense contre les pathogènes. Décrits pendant de nombreuses années qu'à travers leurs fonctions phagocytaires, il s'avère que les macrophages présentent une très grande hétérogénéité phénotypique et fonctionnelle. En effet, l'avènement de nombreuses technologies d'analyses au cours des dernières décennies, couplé à de grands progrès des technologies préexistantes de cytométrie en flux et de microscopie a permis de mettre en avant une importante hétérogénéité des macrophages. Ainsi, il s'avère qu'il existe de nombreuses sous-populations de macrophages dans les tissus caractérisées par l'expression de marqueurs spécifiques. Cette grande diversité peut être expliquée, au moins en partie, par leurs origines et semble être une caractéristique importante qui va grandement influencer les caractéristiques des macrophages. Le micro-environnement joue également un grand rôle sur la diversité des macrophages. De surcroit, il s'avère que le sexe biologique exercerait une influence sur les différents compartiments immunitaires et sur la diversité des cellules myéloïdes. Ces différences pourraient, en partie, expliquer la prévalence plus importante des maladies auto-immunes chez les femmes.Au cours de mes travaux de thèse, nous avons, dans un premier temps, caractérisé finement les macrophages des glandes surrénales, population jusqu'alors non étudiée dans cet organe. Pour cela, nous avons étudié leurs phénotypes avec des technologies dites « single-cell » et leurs origines avec des modèles transgéniques murins. Nous avons observé que les glandes surrénales des souris sont composées de différentes sous-populations de macrophages ayant des origines développementales différentes. De plus, nous avons mis en évidence un dimorphisme sexuel important dans leurs localisations et leurs phénotypes. La déplétion des macrophages semble impacter fortement l'homéostasie des hormones qui y sont synthétisées, ce qui sous-tend leur rôle prépondérant dans l'homéostasie de cet organe. Nous avons ensuite voulu comprendre comment le stress pouvait influencer les différents compartiments immunitaires et avons relevé une différence dans la réponse au stress dit « aigu » et « chronique » entre souris mâles et femelles.Macrophages are innate immune cells found in all organs. Macrophages are the first line of host defense against pathogens. Recently, it was reported that macrophages display great phenotypic and functional heterogeneity. Indeed, the progress of numerous technologies of analysis during the last decades, coupled with the improvement of flow cytometry and microscopy, highlighted heterogeneity in tissue macrophage populations. Thus, the presence of various macrophage subsets characterized by the expression of specific markers was revealed in tissues. This diversity could be explained, at least partially, by their developmental origin. Moreover, the local microenvironment also plays a major role in shaping macrophage diversity. Furthermore, biological sex has been shown to influence myeloid cell diversity. This could account for the increased prevalence of several autoimmune diseases in women.My work was focused on characterizing immune cell diversity in the adrenal glands. We observed that adrenal glands contained multiple macrophage subsets with various developmental origins. Moreover, we highlighted a sexual dimorphism in their location and phenotype. Macrophage depletion had a strong impact on adrenal gland hormones, which underlies their critical role in the maintenance of tissue homeostasis. Finally, we aimed to define how stress could influence the immune cell response and found a difference in immune responses to “acute” and “chronic” stress between males and females

Macrophage metabolic regulation in atherosclerotic plaque

International audienceMetabolism plays a key role in controlling immune cell functions. In this review, we will discuss the diversity of plaque resident myeloid cells and will focus on their metabolic demands that could reflect on their particular intraplaque localization. Defining the metabolic configuration of plaque resident myeloid cells according to their topologic distribution could provide answers to key questions regarding their functions and contribution to disease development

The Adult Adrenal Cortex Undergoes Rapid Tissue Renewal in a Sex-Specific Manner

International audienceEvolution has resulted in profound differences between males and females that extend to non-reproductive organs and are reflected in the susceptibility and progression of diseases. However, the cellular and molecular basis for these differences remains largely unknown. Here we report that adrenal gland tissue renewal is highly active and sexually dimorphic, with female mice showing a 3-fold higher turnover than males. Moreover, in males, homeostasis relies on proliferation of cells within the steroidogenic zone, but females employ an additional stem and/or progenitor compartment situated in the adrenal capsule. Using lineage tracing, sex reversal models, gonadectomy, and dihydrotestosterone treatments, we further show that sex-specific stem cell activity is driven by male hormones that repress recruitment of Gli1+ stem cells from the capsule and cell proliferation. Taken together, our findings provide a molecular and cellular basis for adrenal sex dimorphism that may contribute to the increased incidence of adrenal diseases in females

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health&mdash;such as obesity, fertility disorders and cancers&mdash;by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10&minus;6 M to 10&minus;12 M; cytotoxicity and proliferation were monitored using the IncuCyte&reg; technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10&minus;12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10&minus;6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10&minus;12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens

Brown adipose tissue monocytes support tissue expansion

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling

International audienceTo adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation

Brown adipose tissue monocytes support tissue expansion

International audienceMonocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling

Unravelling the sex-specific diversity and functions of adrenal gland macrophages

International audienceHighlights d Adrenal glands contain multiple macrophage populations d Macrophage sex dimorphism depends on the presence of the cortical X zone d Embryonic and monocyte-derived macrophages co-exist in adrenal gland