Relative adrenal insufficiency as a risk factor and an endotype for sepsis

Summary Sepsis is a major health issue with a mortality rate of 30%. Sepsis induces huge stress responses, including a 5-10 fold induction in glucocorticoid (GC) production in adrenal gland, however, the function of this inducible GC (iGC) remains poorly understood. Importantly, 25-60% of septic patients suffer relative adrenal insufficiency – insufficient iGC production in response to stress. Given the potential complications of adrenal insufficiency, GC therapy is often used for septic shock patients. However, the true contribution of adrenal insufficiency to sepsis and the efficacy of GC therapy are highly controversial. While a number of factors contribute to the debate, a lack of a relative adrenal insufficiency animal model has limited our capacity to address these issues. Toward a solution, scavenger receptor BI (SR-BI), a well-established high density lipoprotein (HDL) receptor, was first identified in our laboratory as a critical protective factor in sepsis. A number of laboratories including ours recently reported that SR-BI null mice fail to produce iGC in response to ACTH stimulation, establishing SR-BI null mice as a relative adrenal insufficiency model. Using this unique model, we demonstrated that mice with relative adrenal insufficiency are susceptible to septic death, and more importantly, supplementation of GC rescued mice with relative adrenal insufficiency, but surprisingly, caused more death in mice without relative adrenal insufficiency. Our findings demonstrate that relative adrenal insufficiency is a risk factor and an endotype of sepsis. Our findings also provide a “proof of concept” to support a precision medicine approach to guide the use of GC for sepsis therapy, specifically, selectively using GC therapy for a subgroup of septic patients with relative adrenal insufficiency. In this R35/MIRA application, we propose to use our newly developed adrenal-specific SR-BI null mice as a unique relative adrenal insufficiency animal model to understand why relative adrenal insufficiency is a risk factor for sepsis and why GC therapy benefits mice with relative adrenal insufficiency, but harms those without. The translation of this study will improve the overall efficacy of sepsis therapy and save lives.