TREM1 deficiency attenuates LPS-induced sepsis-associated acute kidney injury by modulating macrophage polarization.

Abstract

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) drives high mortality in sepsis. The triggering receptor expressed on myeloid cells-1 (TREM1) plays critical roles in both infectious and non-infectious pathologies. However, the role of TREM1 in AKI still needs to be further clarified. METHODS: Using both in vivo and in vitro experiments, we examined the role and underlying mechanism of TREM1 in AKI. RESULTS: In this study, the level of soluble TREM (sTREM1) in the urine of patients with SA-AKI was significantly higher than that of the healthy control group, although there was no significant difference in sTREM1 levels in the serum. In the SA-AKI mouse model, TREM1 deficiency markedly reduced serum creatinine levels in SA-AKI mice. Notably, TREM1 deficiency significantly promoted the expression levels of Il10 and Cd206 in the kidneys of SA-AKI mice. Cytometric Bead Array analysis revealed that serum levels of the pro-inflammatory cytokines IL17A and IFN-γ were significantly diminished, whereas the anti-inflammatory factor IL10 was notably elevated. The enzyme-linked immunosorbent assay (ELISA) results showed that the serum levels of CCL2 and CXCL1 in TREM1-deficient mice were significantly reduced. Mechanistically, experimental evidence indicated that TREM1 deficiency promoted M2 macrophage polarization by activating IRF4 via PI3K/AKT and STAT6 pathways. CONCLUSIONS: These findings confirmed that TREM1 is the primary regulatory factor of macrophage plasticity in SA-AKI, proposing a therapeutic strategy for the clinical intervention of SA-AKI-related kidney diseases.