TY - JOUR
T1 - The PD-1–PD-L1 pathway maintains an immunosuppressive environment essential for neonatal heart regeneration
AU - Vargas Aguilar, Stephanie
AU - Cui, Miao
AU - Tan, Wei
AU - Sanchez-Ortiz, Efrain
AU - Bassel-Duby, Rhonda
AU - Liu, Ning
AU - Olson, Eric N.
N1 - Publisher Copyright:
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.
PY - 2024/3
Y1 - 2024/3
N2 - The adult mouse heart responds to injury by scarring with consequent loss of contractile function, whereas the neonatal heart possesses the ability to regenerate. Activation of the immune system is among the first events upon tissue injury. It has been shown that immune response kinetics differ between regeneration and pathological remodeling, yet the underlying mechanisms of the distinct immune reactions during tissue healing remain unclear. Here we show that the immunomodulatory PD-1–PD-L1 pathway is highly active in regenerative neonatal hearts but rapidly silenced later in life. Deletion of the PD-1 receptor or inactivation of its ligand PD-L1 prevented regeneration of neonatal hearts after injury. Disruption of the pathway during neonatal cardiac injury led to increased inflammation and aberrant T cell activation, which ultimately impaired cardiac regeneration. Our findings reveal an immunomodulatory and cardioprotective role for the PD-1–PD-L1 pathway in heart regeneration and offer potential avenues for the control of adult tissue regeneration.
AB - The adult mouse heart responds to injury by scarring with consequent loss of contractile function, whereas the neonatal heart possesses the ability to regenerate. Activation of the immune system is among the first events upon tissue injury. It has been shown that immune response kinetics differ between regeneration and pathological remodeling, yet the underlying mechanisms of the distinct immune reactions during tissue healing remain unclear. Here we show that the immunomodulatory PD-1–PD-L1 pathway is highly active in regenerative neonatal hearts but rapidly silenced later in life. Deletion of the PD-1 receptor or inactivation of its ligand PD-L1 prevented regeneration of neonatal hearts after injury. Disruption of the pathway during neonatal cardiac injury led to increased inflammation and aberrant T cell activation, which ultimately impaired cardiac regeneration. Our findings reveal an immunomodulatory and cardioprotective role for the PD-1–PD-L1 pathway in heart regeneration and offer potential avenues for the control of adult tissue regeneration.
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U2 - 10.1038/s44161-024-00447-7
DO - 10.1038/s44161-024-00447-7
M3 - Article
AN - SCOPUS:85186422875
SN - 2731-0590
VL - 3
SP - 389
EP - 402
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 3
ER -