The Role of Glucocorticoid Signaling in Lymphopenia After Cardiac Arrest in Mice
Abstract Body: Background Cardiac arrest (CA) is a leading cause of morbidity and mortality in the US. There is an urgent need for improvements not only in resuscitation, but also in post-CA treatment and care. A critical element of post-CA pathophysiology is the dysregulation of the immune system, which likely contributes to an increased risk of infectious complications in CA patients. Indeed, both clinical and experimental evidence indicates that after an initial hyperinflammatory response, an immunosuppressive phase ensues, characterized by a marked reduction in lymphocytes (lymphopenia). Notably, lymphopenia has been associated with poor prognosis after CA, representing a potential therapeutic target for intervention. However, our understanding of how post-CA lymphopenia progresses is limited, and the underlying mechanisms remain largely unknown.
Methods Young (3-6 months old) and aged (19-22 months old) mice were subjected to KCl-induced CA followed by cardiopulmonary resuscitation. RU486, a glucocorticoid receptor (GR) antagonist, was used to suppress glucocorticoid signaling. Conditional knockout mice with T cell- or B cell-specific GR deletion were generated and exploited. Flow cytometry analysis was performed to characterize immune cell populations.
Results First, we performed a time-course study (day 1-14 post CA) to establish temporal changes of lymphocytes in the thymus (T cells) and bone marrow (BM; B cells) using flow cytometry. Our data indicated that double positive (DP) thymocytes were drastically depleted by day 3 post-CA, and the defects largely recovered by post-CA day 7. In the BM, a reduction in developmental B cells was observed, particularly with the near absence of the pre-B population on post-CA day 3. The impairment of B cell development was still evident on day 7, but was fully reversed by day 14 after CA. Similar immune impairments were confirmed in female and aged mice. Next, our data demonstrated that these immune defects can be partially rescue by post-CA RU486 treatment. Lastly, we found that specific deletion of GR in T or B cells improved the homeostasis of developmental T or B cells in the thymus or BM, respectively.
Conclusions Our findings underscore the critical role of glucocorticoid signaling in mediating post-CA lymphopenia. Thus, targeting this pathway may represent an immunomodulatory therapy to advance post-resuscitation care and improve the prognosis for CA survivors.
Del Aguila, Angela
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Dang, Lihong
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Zhang, Ran
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Zhang, Jin
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Rehman, Ata
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Xu, Feng
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Sheng, Huaxin
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Yang, Wei
( DUKE UNIVERSITY MEDCIAL CENTER
, Durham
, North Carolina
, United States
)
Author Disclosures:
Angela del Aguila:No Answer
| Lihong Dang:DO NOT have relevant financial relationships
| Ran Zhang:No Answer
| Jin Zhang:No Answer
| Ata Rehman:No Answer
| Feng Xu:No Answer
| Huaxin Sheng:No Answer
| Wei Yang:DO NOT have relevant financial relationships