TY - JOUR
T1 - The adrenal stress response is an essential host response against therapy-induced lethal immune activation
AU - Guo, Ling
AU - Wang, Weinan
AU - Wang, Qian
AU - Hao, Dan
AU - Ito, Misa
AU - Huang, Bin
AU - Mineo, Chieko
AU - Shaul, Philip W.
AU - Choi, Jaebok
AU - Frank Huang, L.
AU - Li, Xiang An
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/3/21
Y1 - 2023/3/21
N2 - Cytokine release syndrome (CRS) is a systemic inflammatory syndrome associated with infection- or druginduced T cell activation and can cause multiple organ failure and even death. Because current treatments are ineffective in some patients with severe CRS, we set out to identify risk factors and mechanisms behind severe CRS that might lead to preventive therapies and better clinical outcomes in patients. In mice, we found that deficiency in the adrenal stress response-with similarities to such in patients called relative adrenal insufficiency (RAI)-conferred a high risk for lethal CRS. Mice treated with CD3 antibodies were protected against lethal CRS by the production of glucocorticoids (GC) induced by the adrenal stress response in a manner dependent on the scavenger receptor B1 (SR-BI), a receptor for high-density lipoprotein (HDL). Mice with whole-body or adrenal gland-specific SR-BI deficiency exhibited impaired GC production, more severe CRS, and increased mortality in response to CD3 antibodies. Pretreatment with a low dose of GC effectively suppressed the development of CRS and rescued survival in SR-BI-deficient mice without compromising T cell function through apoptosis. Our findings suggest that RAI may be a risk factor for therapy-induced CRS and that pretreating RAI patients with GC may prevent lethal CRS.
AB - Cytokine release syndrome (CRS) is a systemic inflammatory syndrome associated with infection- or druginduced T cell activation and can cause multiple organ failure and even death. Because current treatments are ineffective in some patients with severe CRS, we set out to identify risk factors and mechanisms behind severe CRS that might lead to preventive therapies and better clinical outcomes in patients. In mice, we found that deficiency in the adrenal stress response-with similarities to such in patients called relative adrenal insufficiency (RAI)-conferred a high risk for lethal CRS. Mice treated with CD3 antibodies were protected against lethal CRS by the production of glucocorticoids (GC) induced by the adrenal stress response in a manner dependent on the scavenger receptor B1 (SR-BI), a receptor for high-density lipoprotein (HDL). Mice with whole-body or adrenal gland-specific SR-BI deficiency exhibited impaired GC production, more severe CRS, and increased mortality in response to CD3 antibodies. Pretreatment with a low dose of GC effectively suppressed the development of CRS and rescued survival in SR-BI-deficient mice without compromising T cell function through apoptosis. Our findings suggest that RAI may be a risk factor for therapy-induced CRS and that pretreating RAI patients with GC may prevent lethal CRS.
UR - http://www.scopus.com/inward/record.url?scp=85150667588&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150667588&partnerID=8YFLogxK
U2 - 10.1126/scisignal.add4900
DO - 10.1126/scisignal.add4900
M3 - Article
C2 - 36943922
AN - SCOPUS:85150667588
SN - 1945-0877
VL - 16
JO - Science Signaling
JF - Science Signaling
IS - 777
M1 - eadd4900
ER -