PD-1/PD-L1 inhibits M1 polarization of microglia and macrophages through STAT1/NF-κB and Akt/mTOR signaling pathways

Inflammatory response following central nervous system (CNS) injury is a significant, multifaceted process that requires further studies. Microglia and macrophages play key roles in CNS inflammation. However, it is still undefined what activity PD-1 plays in M1 polarization and what mechanisms PD-1 regulates the polarization of microglia and macrophages. This study was design to determine whether PD-1 influences M1 polarization of microglia and macrophages and explore PD-1 regulatory mechanisms in M1 polarization using the model mouse and proteomics analysis.

It applied six newborn and sixty 6-8 week-old C57BL/6 mice, sixty PD-1 knockout (KO) mice, sixty PD-L1 KO mice, and fifteen PD-1 over-expressed mice.

Our studies have shown that programmed death-1 (PD-1) is upregulated in microglia and macrophages in spinal cord injury (SCI), and polarized stimulation induces the expression of PD-1 in cultured microglia and macrophages. We have also observed that following SCI in a PD-1 KO model mouse, there is an increase in M1 polarization of macrophages. PD-1 and PD-L1 were upregulated with M1 polarization in peritoneal macrophages, Raw 264.7 and cerebral cortex-derived microglia, and M1 polarization was inhibited by PD-1 and PD-L1 through STAT1/NF-κB and Akt/mTOR signaling pathways in bone marrow-derived macrophages of PD-1 KO and PD-L1 KO mice.

This study supported that PD-1/PD-L1 inhibits M1 polarization of microglia and macrophages through STAT1/NF-κB and Akt/mTOR signaling pathways. PD-1 regulated M1 polarization could be a key clinical target of novel immune-focused therapeutic strategies for CNS injury and inflammatory response.