How stress triggers inflammation

Acute stress seems to amplify inflammatory disease despite the fact many stress hormones such as cortisol actually suppress the immune system. Qing et al. show that this is because the rise in adrenaline (epinephrine) and norepinephrine levels during acute stress triggers the release of the pro-inflammatory cytokine interleukin-6 (IL-6) by brown fat cells. IL-6 is the signal for liver release of the glucose needed for the fight or flight response, but this comes at the cost of enhancing mortality to a subsequent inflammatory challenge. Here is their abstract:

Highlights

• 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

Summary

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.