Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.
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2021-05
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In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.
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Zhao, Qiang, Yuntian Shen, Ran Li, Jiangbo Wu, Jingjun Lyu, Maorong Jiang, Liping Lu, Minghua Zhu, et al. (2021). Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 41(5). pp. 1091–1102. 10.1177/0271678x20948612 Retrieved from https://hdl.handle.net/10161/23237.
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Scholars@Duke
Huaxin Sheng
Weiguo Zhang
Activation via the T-cell antigen receptor (TCR) triggers a cascade of intracellular biochemical events eventually leading to T-cell proliferation and effector functions. One of the earliest events is the activation of the Src family tyrosine kinases Fyn and Lck. The activated Src family kinases phosphorylate the CD3 subunits and TCRζ chains. ZAP-70 tyrosine kinase is recruited to the antigen receptors via the binding to CD3 and TCRζ. ZAP-70 is then tyrosine phosphorylated by these Src family kinases and thus activated. These activated tyrosine kinases further phosphorylate a number of intracellular proteins, such as PLC-γ1, Vav, Cbl, SLP-76, and LAT, and activate downstream signaling pathways including the Ras-MAPK pathway and Ca2+flux. Activation of these two pathways is required for AP-1 and NFAT-mediated transcription, IL-2 production, and T-cell proliferation.
Our primary interest of the laboratory is to understand the role of membrane-associated adaptor proteins in lymphocyte activation, development, and immune response. One of these proteins is LAT (Linker for Activation of T-cells). LAT is tyrosine phosphorylated upon T-cell activation and associates with several signaling molecules including Grb2, Gads, and PLC-γ1. LAT-deficient T-cells are defective in the Ras-MAPK activation and Ca2+ flux after the TCR engagement. LAT knockout mice have an early block in thymocyte development. Interestingly, mice with a mutation in LAT develop a severe autoimmune disease. We are investigating how LAT interacts with other signaling proteins and how LAT regulates T cell activation and immune responses.
In addition to LAT, we are working on two LAT-like molecules, LAB and LAX. We have generated mice deficient in these proteins and are analyzing the phenotypes of these mice to determine the role of these proteins in lymphocyte signaling and immune responses.
We are also interested in FcεRI-mediated signaling. We are working on the role of LAT, LAB, and RasGRP1 in FcεRI-mediated signaling, mast cell function, and allergic responses.
Our long-term goal is to understand the details of immunoreceptor-mediated signaling pathways. Understanding these signaling pathways may identify therapeutic targets that could facilitate the development of drugs that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, and cancer.
Wei Yang
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