Reduced Neutrophil Extracellular Trap Formation During Ischemia Reperfusion Injury in C3 KO Mice: C3 Requirement for NETs Release.

Xiaoting Wu, Danyu You, Jiong Cui, Liyan Yang, Liyu Lin, Yi Chen, Changsheng Xu, Guili Lian, Jianxin Wan

Frontiers in immunology 2022

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Complement C3 plays a prominent role in inflammatory processes, and its increase exacerbates ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI). Infiltrated neutrophils can be stimulated to form neutrophil extracellular traps (NETs), leading to renal injury. However, the relationship between the increase of C3 and the release of NETs in AKI was not clear. Here we found that IRI in the mouse kidney leads to increased neutrophils infiltration and NET formation. Furthermore, neutrophils depletion by anti-Ly6G IgG (1A8) did not reduce C3 activation but reduced kidney injury and inflammation, indicating a link between neutrophils infiltration and renal tissue damage. Pretreatment with 1A8 suppressed ischemia-induced NET formation, proving that extracellular traps (ETs) in renal tissue were mainly derived from neutrophils. Renal ischemia injury also leads to increased expression of C3. Moreover, C3 KO mice (C3 KO) with IRI exhibited attenuated kidney damage and decreased neutrophils and NETs. In vitro, C3a primed neutrophils to form NETs, reflected by amorphous extracellular DNA structures that colocalized with CitH3 and MPO. These data reveal that C3 deficiency can ameliorate AKI by reducing the infiltration of neutrophils and the formation of NETs. Targeting C3 activation may be a new therapeutic strategy for alleviating the necroinflammation of NETs in AKI. Copyright © 2022 Wu, You, Cui, Yang, Lin, Chen, Xu, Lian and Wan.

Citation

Xiaoting Wu, Danyu You, Jiong Cui, Liyan Yang, Liyu Lin, Yi Chen, Changsheng Xu, Guili Lian, Jianxin Wan. Reduced Neutrophil Extracellular Trap Formation During Ischemia Reperfusion Injury in C3 KO Mice: C3 Requirement for NETs Release. Frontiers in immunology. 2022;13:781273