Abstract
Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We assessed the contribution of the PD-1 pathway to regulating the polarization of macrophages that promote inflammation induced by zymosan. We found that PD-1−/− mice developed robust peritonitis with more abundant infiltration of M1 macrophages, accompanied by higher levels of pro-inflammation factors, especially monocyte chemotactic protein-1 (MCP-1) compared with wild-type controls ex vivo and in vitro. Our results indicated that PD-1 deficiency promotes M1 rather than M2 polarization of macrophages by enhancing the expression of p-STAT1/p-NF-κB p65 and downregulating p-STAT6. We found that PD-1 engagement followed by zymosan stimulation might primarily attenuate the phosphorylation of tyrosine residue in PD-1 receptor/ligand and the recruitment of SHP-2 to PD-1 receptor/ligand, leading to the reduction of M1 type cytokine production.
Highlights
‘macrophage disappearance reaction’,11 Large peritoneal macrophages (LPM) frequencies dwindled to less than 10% after 48 h stimulation (8.4 ± 1.8%), and were kept at a low level until 72 h (5.3 ± 1.6%); Small peritoneal macrophages (SPM) became the dominant subset in the peritoneal cavity (36.0 ± 3.4%) at 4 h and decreased at 48 and 72 h, but SPMs were the main population during the whole phase after simulation
The percentage of SPMs was kept at a higher level during the whole phase after zymosan stimulation than that in WT mice; the infiltration of monocytes was delayed until 48 h (0.7 ± 0.2%) after injection, and increased gradually at 72 h (1.6 ± 0.4%); interestingly, we did not find infiltration of neutrophils in KO mice
We found that the macrophage/monocyte population after zymosan stimulation shifted with time toward expression of the SPM phenotype
Summary
Received 11.12.15; revised 17.1.16; accepted 26.1.16; Edited by H-U Simon important role on the polarization of macrophages/monocytes in peritoneal cavity to exert significant anti-inflammatory and atheroprotective effects has not been studied previously. We found that PD-1 deficiency promoted M1 polarization of macrophages/monocytes and exacerbated inflammation induced by zymosan via enhancing the phosphorylation of STAT1/p-NF-κB p65. We demonstrated that PD-1 engagement followed by zymosan stimulation might primarily attenuate the phosphorylation of tyrosine residue in PD-1 receptor and the recruitment of SHP-2 to PD-1 receptor, leading to the reduction of M1 type cytokine production
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