1. Introduction
Various cells exist in the adrenal glands besides steroid hormone-producing cells. With recent advances in analytical techniques, it has become clear that macrophages present in the adrenal glands regulate the amount of hormones produced by the adrenal cortex. Macrophages are a type of immune cell that patrol the body, find and ingest bacteria and viruses to dispose of them. Adrenocortical hormones are known to increase to about 10 times their normal levels when the body is attacked by bacteria or viruses. Macrophages in the adrenal glands play a role in rapidly increasing adrenocortical hormone levels in such situations, and have also been reported to have the function of finely regulating to prevent excessive increases in adrenocortical hormones.
In congenital lipoid adrenal hyperplasia, macrophages are known to accumulate in the adrenal glands and gonads. By studying the function of macrophages in such pathological states, new therapeutic strategies to restore hormone production capacity of the adrenal glands and gonads may be discovered. We introduce three recent basic research studies using mice.
2. Diversity and function of adrenal macrophages with sex-specific characteristics
Although macrophages work throughout the body, little was known about the types, origins, and roles of macrophages in the adrenal glands. The authors of this paper used a cutting-edge technique called single-cell RNA sequencing to investigate the diversity of immune cells in the adrenal glands, and explored how these cells develop using genetic manipulation methods.
As a result, they found that adrenal macrophages come in two types: those derived from monocytes and those present from the embryonic stage. They also discovered a type specific to female mice with low levels of a specific molecule (MHC class II). In adult mice, new macrophages were found to be replenished by monocytes in female mouse adrenal glands. The distribution of adrenal macrophages differs by sex, with macrophages low in MHC class II particularly concentrating in a specific location in the adrenal glands (the boundary between cortex and medulla). This sex difference is related to the "cortical X zone," part of the adrenal gland. When adrenal macrophages decrease, body homeostasis is disturbed and aldosterone production during stress decreases. These data revealed that adrenal macrophages are diverse, with sex-based differences in their distribution and function.
Reference: Dolfi B, et al. Cell Rep 2022; 39: 110949
3. Adrenal macrophages regulate glucocorticoid production via Trem2 and TGFβ
The adrenal glands produce hormones (glucocorticoids) when under stress, and this process is regulated by the hypothalamus and pituitary in the brain. Recent research has suggested that immune cells called macrophages may be involved in this hormone production, but the specific mechanism was unclear. This study investigated the role of adrenal macrophages in response to acute or chronic stress such as cold exposure or inflammation from atherosclerosis. Using single-cell RNA sequencing technology, they observed in detail how adrenal macrophages change when under stress.
As a result, they found that stress causes adrenal macrophages to change to a specific activation state. Particularly important was that a protein called Trem2 increased significantly after stress. When they investigated what would happen if this Trem2 was deleted from macrophages, they found the following: 1) the number of macrophages decreased, 2) the ability of macrophages to produce another important molecule called TGFβ was lost, and 3) glucocorticoid production increased. Furthermore, it was confirmed that inhibiting the action of TGFβ also increased glucocorticoid production.
These results showed that adrenal macrophages control hormone production through Trem2 and TGFβ. This discovery may lead to the development of new treatments for stress-related disorders targeting the immune system.
Reference: Xu Y, et al. JCI Insight 2024; 9: e174746
4. Adrenal macrophages regulate corticosteroid production
Although it has been known for over 30 years that "macrophages" exist in the adrenal glands, their role was unclear. Because macrophages in other tissues have been found to perform various physiological roles beyond immune function, it was thought that adrenal macrophages might also have unknown functions.
This study revealed that two different types of macrophages exist in the adrenal glands. The first is dendritic cell-like macrophages seen in both young and old mice, distributed throughout the adrenal glands. The second is "foamy" macrophages containing abundant fat that increase with age and diet, accumulating mainly in the outer part of the adrenal glands (cortex). Particularly interesting is the function of these "foamy" macrophages. These macrophages were found to accumulate cholesterol and thereby regulate the secretion amount of adrenal hormones. This regulatory function works not only under normal conditions but also in obesity.
This discovery shows a new aspect of the mechanisms that maintain our body's hormonal balance. It was revealed that adrenal macrophages are not merely immune cells but play the important physiological function of regulating hormone secretion. These research results may deepen understanding of stress-related disorders and health problems related to obesity, potentially leading to the development of new treatments. Also, by deepening understanding of adrenal hormone production mechanisms, it is expected to contribute to elucidating various symptoms and disorders related to hormonal imbalances.
Reference: O'Brien CJO, et al. bioRxiv 2023