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Inhibition of PD-1 Alters the SHP1/2-PI3K/Akt Axis to Decrease M1 Polarization of Alveolar Macrophages in Lung
Xiaojing He1,2,3,4, Jingyuan Xiao1,2,3,4, Zhao Li5
1Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China.
Abstract:
Polarization of alveolar macrophages (AMs) into the M1 phenotype contributes to inflammatory responses and tissue damage that occur during lung ischemia-reperfusion injury (LIRI). Programmed cell death factor-1 (PD-1) regulates polarization of macrophages, but its role in LIRI is unknown. We examined the role of PD-1 in AM polarization in models of LIRI in vivo and in vitro. Adult Sprague-Dawley rats were subjected to ischemia-reperfusion with or without pretreatment with a PD-1 inhibitor, SHP1/2 inhibitor, or Akt activator. Lung tissue damage and infiltration by M1-type AMs were assessed. As an in vitro complement to the animal studies, rat alveolar macrophages in culture were subjected to oxygen/glucose deprivation and reoxygenation. Levels of SHP1/2 and Akt proteins were evaluated using Western blots, while levels of pro-inflammatory cytokines were measured using enzyme-linked immunosorbent assays. Injury upregulated PD-1 both in vivo and in vitro. Inhibiting PD-1 reduced the number of M1-type AMs, expression of SHP1 and SHP2, and levels of inflammatory cytokines. At the same time, it partially restored Akt activation. Similar results were observed after inhibition of SHP1/2 or activation of the PI3K/Akt pathway. PD-1 promotes polarization of AMs to the M1 phenotype and inflammatory responses through the SHP1/2-PI3K/Akt axis. Inhibiting PD-1 may be an effective therapeutic strategy to limit LIRI.
Insights
Programmed cell death factor-1 (PD-1) drives M1 polarization in lung ischemia-reperfusion injury (LIRI). Inhibiting PD-1 reduces inflammation and tissue damage by modulating the SHP1/2-PI3K/Akt pathway, offering a potential LIRI therapy.
Area of Science:
- Immunology
- Pulmonology
- Cell Biology
Background:
- Alveolar macrophage (AM) M1 polarization exacerbates lung ischemia-reperfusion injury (LIRI).
- Programmed cell death factor-1 (PD-1) influences macrophage polarization, but its role in LIRI remains unclear.
Purpose of the Study:
- To investigate the role of PD-1 in AM polarization during LIRI.
- To elucidate the underlying molecular mechanisms involving PD-1 in LIRI.
Main Methods:
- In vivo rat models of LIRI with PD-1 inhibition, SHP1/2 inhibition, or Akt activation.
- In vitro studies using rat AMs subjected to oxygen/glucose deprivation and reoxygenation.
- Assessment of lung tissue damage, M1 AM infiltration, protein levels (SHP1/2, Akt), and cytokine levels.
Main Results:
- LIRI upregulated PD-1 expression in vivo and in vitro.
- PD-1 inhibition decreased M1 AMs, SHP1/2 expression, and inflammatory cytokines, while restoring Akt activation.
- SHP1/2 inhibition or Akt activation mimicked the protective effects of PD-1 inhibition.
Conclusions:
- PD-1 promotes M1 AM polarization and inflammation in LIRI via the SHP1/2-PI3K/Akt pathway.
- Targeting PD-1 presents a promising therapeutic strategy for mitigating LIRI-associated lung damage.
