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Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
C-176 inhibits macrophage polarization towards M1-subtype and ameliorates LPS induced acute kidney injury
Xiao Leng1, Qirui Li2, Wanqi Chen3
1School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Center for Scientific Research, Chengdu Medical College, Chengdu, China; Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China.
Abstract:
Sepsis-induced acute kidney injury (SI-AKI) has become a focal point in nephrology research field due to its high mortality and potential progression to chronic kidney disease (CKD). The increase of M1 macrophages within renal tissue and their associated inflammatory responses are key contributors to renal inflammation and subsequent damage. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is abnormally activated during the onset of acute kidney injury (AKI). However, the relationship between the activation of this pathway and the increase in M1 macrophages has not been fully elucidated. This study investigated the protective effects and underlying mechanisms of the STING pathway-specific inhibitor C-176 on LPS-induced AKI, using an LPS and IFN-γ induced M1 macrophage model and an LPS-induced sepsis AKI mouse model. The in vivo results demonstrate that C-176 intervention can alleviate acute kidney injury and improve renal function by reducing macrophage infiltration in renal tissue, decreasing the proportion of M1 macrophages, and mitigating the inflammatory response. Additionally, in vitro results indicate that C-176 intervention inhibits the polarization of M0 macrophages to M1 macrophages, promotes their polarization to M2 macrophages, and reduces the amounts of pro-inflammatory cytokines such as IL-6 and TNF-α at both the protein and gene expression levels. The biological effects of C-176 are associated with the inhibition of STING-IRF3 signaling pathway activation. In summary, the findings of this study have certain scientific significance and application value for exploring the pathogenesis and treatment methods of SI-AKI.
Insights
The STING pathway inhibitor C-176 protects against sepsis-induced acute kidney injury (SI-AKI) by reducing M1 macrophage polarization and inflammation. This study highlights C-176 as a potential therapeutic for SI-AKI and related kidney diseases.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Sepsis-induced acute kidney injury (SI-AKI) is a critical condition with high mortality and progression risk to chronic kidney disease (CKD).
- M1 macrophages and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway are implicated in renal inflammation during AKI.
- The interplay between STING pathway activation and M1 macrophage increase in SI-AKI requires further elucidation.
Purpose of the Study:
- To investigate the protective effects of the STING pathway inhibitor C-176 on lipopolysaccharide (LPS)-induced acute kidney injury (AKI).
- To elucidate the underlying mechanisms of C-176 action, focusing on macrophage polarization and inflammatory responses.
Main Methods:
- Utilized an LPS and interferon-gamma (IFN-γ) induced M1 macrophage model and an LPS-induced sepsis AKI mouse model.
- Administered C-176 in vivo and in vitro to assess its impact on renal function, macrophage infiltration, and polarization.
- Analyzed pro-inflammatory cytokine levels (IL-6, TNF-α) and STING-IRF3 signaling pathway activation.
Main Results:
- C-176 intervention alleviated kidney injury and improved renal function in the mouse model.
- C-176 reduced macrophage infiltration, decreased M1 macrophage proportion, and mitigated renal inflammation.
- In vitro, C-176 inhibited M0 to M1 macrophage polarization, promoted M2 polarization, and reduced pro-inflammatory cytokines by suppressing STING-IRF3 signaling.
Conclusions:
- C-176 demonstrates protective effects against LPS-induced AKI by modulating macrophage polarization and inflammatory signaling.
- Inhibition of the STING pathway is a viable therapeutic strategy for SI-AKI.
- Findings offer insights into SI-AKI pathogenesis and potential treatment avenues.
