Origin and Function of Stress-Induced IL-6 in Murine Models

• Published in: Cell Vol. 182; no. 2; pp. 372 - 387.e14
• Main Authors: Qing, Hua, Desrouleaux, Reina, Israni-Winger, Kavita, Mineur, Yann S., Fogelman, Nia, Zhang, Cuiling, Rashed, Saleh, Palm, Noah W., Sinha, Rajita, Picciotto, Marina R., Perry, Rachel J., Wang, Andrew
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2020
• Subjects: acute stress; Adipose Tissue, Brown - metabolism; animal models; Animals; beta-adrenergic receptors; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; Brain - metabolism; brown adipocytes; brown adipose tissue; Chemokines - metabolism; Cytokines - metabolism; Disease Models, Animal; Gluconeogenesis; hyperglycemia; Hyperglycemia - metabolism; Hyperglycemia - pathology; IL-6; immunometabolism; inflammation; interleukin-6; Interleukin-6 - blood; Interleukin-6 - genetics; Interleukin-6 - metabolism; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mortality; neuroendocrine-immune axis; neuroimmunology; ontogeny; psychological stress; Receptors, Adrenergic, beta-3 - metabolism; Receptors, Interleukin-6 - metabolism; Stress, Psychological; tolerance; Uncoupling Protein 1 - deficiency; Uncoupling Protein 1 - genetics; neuroimmunology; brown adipose tissue; immunometabolism; inflammation; acute stress; beta-adrenergic receptors; gluconeogenesis; neuroendocrine-immune axis; IL-6; tolerance
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.05.054

Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases. [Display omitted] •IL-6 is the dominant endocrine cytokine induced by acute stress in mice•Stress-inducible IL-6 is produced in brown adipocytes via ADRB3 signaling•IL-6 is required for stress hyperglycemia and adaptive “fight or flight” responses•Stress-induced IL-6 decreases tolerance to a subsequent inflammatory challenge During acute psychological stress, brown adipocytes initiate a chain of events mediated by adrenergic signaling and IL-6 release that metabolically fuels “fight or flight” adaptive responses but at the same time comes at an inflammatory cost.