Immune cells and cytokine circuits: toward a working model for understanding direct immune-to-adrenal communication pathways.

Although the adrenal glands were anatomically identified nearly 450 yr ago, their vital role in physiology was not established until considerably later (1). We now know that the adrenal glands, despite their miniature size, play an indispensable role in homeostatic functions ranging from regulation of ion balances to being a final site of integration for the stress response. When considering the many masters that oversee adrenal output, most people can readily recite three principle sources of adrenal regulation: 1) the kidney, which regulates mineralocorticoid secretion through the renin-angiotensin system; 2) the pituitary gland, which regulates glucocorticoid secretion via ACTH; and 3) the splanchnic nerve, which regulates blood flow to the adrenal and innervates the medulla, thereby regulating secretion of catecholamines and other stress-responsive factors into systemic circulation. The adrenal glands have earned further recognition as key modulators of immune function, because secretory products of the adrenal glands (particularly glucocorticoids and catecholamines) tightly regulate cytokine expression (2, 3), immune cell activation (4, 5), and even bacterial proliferation (6). However, the impact of immune stimulation on adrenal output has been largely focused on neuroendocrine pathways involving the traditional hypothalamic-pituitary-adrenal (HPA) cascade (CRH3ACTH3glucocorticoid) (7–9). Only in recent years have we come to recognize that immune stimuli can directly and independently regulate adrenal function as well (10, 11) (see Fig. 1), suggesting a mechanism to explain the dissociation between plasma concentrations of ACTH and glucocorticoids that has often been noted after immune challenge (12, 13). This latter pathway—mechanisms of direct immuneto-adrenal signaling—is the subject of the manuscript by Engstrom et al. (14) in this issue of Endocrinology. Briefly, the authors examined morphological and functional characteristics of two key immune cells (dendritic cells and macrophages) in the adrenal gland after systemic injection of lipopolysaccharide (LPS), a common model of bacterial infection. Although their experimental preparation was simple, the approach was clever and the outcome was fascinating. Both of these immune cells are derived from the myeloid lineage and function primarily as professional antigen-presenting cells, thereby forming the backbone for the innate immune response. To do this, adrenal glands were collected, sliced, and stained with antibodies directed against ED1, a cell surface marker for myeloid cells, and OX6, which labels major histocompatibility complex class II (MHCII). Additionally, cells were colabeled for inflammatory-related signaling factors targeting the IL-1 and prostaglandin families. The real strength of the experiment, however, comes from the authors’ exquisite attention to the time course of inflammatory-related changes, which revealed two fascinating stories. The first story reads very much like a chapter from a classic immunology textbook. Their results indicated that antigen is engulfed by mature resident dendritic cells, bundled inside the cell with MHCII, and transferred to the cell surface. At the same time, cytoskeletal rearrangements allow for the activated dendritic cells to migrate back into the bloodstream where they travel to the draining lymph node, present the antigen/MHCII complex to T and B cells, thereby eliciting cell-mediated and humoral immune responses, respectively. In this regard, dendritic cells of the adrenal glands are serving, quite literally, as a vehicle that carries its cargo (LPS) from the site of infection (adrenals) to the immune cell depot (lymph nodes). Not to be