Adrenal gland macrophages regulate glucocorticoid production through Trem2 and TGF-β
Yingzheng Xu, Michael T. Patterson, Bastien Dolfi, Alisha Zhu, Adeline Bertola, Patricia R. Schrank, Alexandre Gallerand, Ainsley E. Kennedy, Hannah Hillman, Lynn Dinh, Sia Shekhar, Samuel Tollison, Tyler D. Bold, Stoyan Ivanov, Jesse W. Williams
Yingzheng Xu, Michael T. Patterson, Bastien Dolfi, Alisha Zhu, Adeline Bertola, Patricia R. Schrank, Alexandre Gallerand, Ainsley E. Kennedy, Hannah Hillman, Lynn Dinh, Sia Shekhar, Samuel Tollison, Tyler D. Bold, Stoyan Ivanov, Jesse W. Williams
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Research Article Endocrinology Immunology

Adrenal gland macrophages regulate glucocorticoid production through Trem2 and TGF-β

Abstract

Glucocorticoid synthesis by adrenal glands (AGs) is regulated by the hypothalamic-pituitary-adrenal axis to facilitate stress responses when the host is exposed to stimuli. Recent studies implicate macrophages as potential steroidogenic regulators, but the molecular mechanisms by which AG macrophages exert such influence remain unclear. In this study, we investigated the role of AG macrophages in response to cold challenge or atherosclerotic inflammation as physiologic models of acute or chronic stress. Using single-cell RNA sequencing, we observed dynamic AG macrophage polarization toward classical activation and lipid-associated phenotypes following acute or chronic stimulation. Among transcriptional alterations induced in macrophages, triggering receptor expressed on myeloid cells 2 (Trem2) was highlighted because of its upregulation following stress. Conditional deletion of macrophage Trem2 revealed a protective role in stress responses. Mechanistically, Trem2 deletion led to increased AG macrophage death, abolished the TGF-β–producing capacity of AG macrophages, and resulted in enhanced glucocorticoid production. In addition, enhanced glucocorticoid production was replicated by blockade of TGF-β signaling. Together, these observations suggest that AG macrophages restrict steroidogenesis through Trem2 and TGF-β, which opens potential avenues for immunotherapeutic interventions to resolve stress-related disorders.

Authors

Yingzheng Xu, Michael T. Patterson, Bastien Dolfi, Alisha Zhu, Adeline Bertola, Patricia R. Schrank, Alexandre Gallerand, Ainsley E. Kennedy, Hannah Hillman, Lynn Dinh, Sia Shekhar, Samuel Tollison, Tyler D. Bold, Stoyan Ivanov, Jesse W. Williams

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Figure 2

Stress promotes AG macrophage turnover.

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Stress promotes AG macrophage turnover. (A) Monocyte-macrophage pseudoti...
(A) Monocyte-macrophage pseudotime trajectory during stress stimulations. (B) Proportion of Ccl2+ monocytes and macrophages. (C) Schematic of fate mapping under chronic stress using control (chow-fed) or atherogenic CCR2creER R26TdTomato Ldlr–/– mice. All mice received 1 dose of TAM and were sacrificed at 2 and 5 days after TAM administration. (D) Percentage of TdTomato+ macrophages (CD11b+CD64+F4/80+) at day 2 and 5 after TAM induction. D2: day 2 after TAM, control (white, CCR2creER R26TdTomato, chow) or atherogenic (black, CCR2creER R26TdTomato Ldlr–/–, HFD) mice, n = 5 in each group. D5: day 5 after TAM, control (white, CCR2creER R26TdTomato, chow, n = 5) or atherogenic (black, CCR2creER R26TdTomato Ldlr–/–, HFD, n = 6) mice. Significance determined by Student’s t test, *P < 0.05. (E) Schematic of fate mapping under acute stress using CCR2creER R26TdTomato mice. Mice fed on chow diet received 1 dose of TAM and cold housing the same day and were housed for 2 days. (F) Percentage of TdTomato+ macrophages after 2 days of cold housing or room temperature (RT). RT (white): male mice housed at RT, n = 6. Cold (white): cold-housed male mice, n = 6. RT (black): female mice housed at RT, n = 7. Cold (black): cold-housed female mice, n = 7. Significance determined by Student’s t test, ***P < 0.001. (G) Absolute AG macrophage (CD11b+CD64+MerTK+F4/80+) number at steady state or stress setting. Steady: B6 mice, n = 22. Ldlr–/–: chow-fed Ldlr–/– mice, n = 3. Cold: B6 mice cold-housed for 2 days, n = 9. Ldlr–/– HFD: Ldlr–/– mice fed 8 weeks of HFD, n = 14. Significance determined by ANOVA, *P < 0.05, ****P < 0.0001. (H) Flow cytometry measurement of AG macrophage (CD11b+CD64+MerTK+F4/80+) caspase-3 during chronic stress. Steady: B6 mice, n = 8. HFD: Ldlr–/– mice fed 8 weeks of HFD, n = 8. Significance determined by Student’s t test, **P < 0.005. Panels D and F–H are presented as mean ± SEM.