Chemokine CCL2 from proximal tubular epithelial cells contributes to sepsis-induced acute kidney injury.

Damage-associated molecular patterns secreted from activated kidney cells initiate the inflammatory response, a critical step in the development of sepsis-induced acute kidney injury (AKI). However, the underlying mechanism remains to be clarified. Here, we established a mouse model of sepsis-induced AKI through intraperitoneal injection of lipopolysaccharide (LPS) and demonstrated that LPS induced dramatical upregulation of C-C motif chemokine ligand 2 (CCL2) at both the mRNA and protein levels in the kidney, which was mainly expressed by tubular epithelial cells (TECs), especially by proximal TECs. Proximal tubule-specific ablation of CCL2 reduced LPS-induced macrophage infiltration, proinflammatory cytokine expression, and attenuated AKI. In vitro, using a Transwell migration assay, we found that deficiency of CCL2 in TECs decreased macrophage migration ability. However, myeloid-specific depletion of CCL2 could not protect the kidneys from the aforementioned effects. Mechanistically, LPS activated Toll-like receptor (TLR)2 signaling in TECs, which induced activation of its downstream effector NF-κB. Blockade of TLR2 signaling or inhibition of NF-κB activation in TECs significantly suppressed LPS-induced CCL2 expression. Furthermore, chromatin immunoprecipitation analyses confirmed a direct binding of NF-κB p65 in the CCL2 promoter region, and LPS increased the binding of NF-κB p65 to the CCL2 promoter, suggesting that TLR2/NF-κB p65 regulates CCL2 expression in TECs. Together, these results demonstrate that endogenous CCL2 released from proximal TECs, not from myeloid cells, was responsible for sepsis-induced kidney inflammation and AKI. Specifically targeting tubular TLR2/NF-κB/CCL2 signaling may be a potential therapeutic strategy for the prevention or attenuation of septic AKI. This study provides a mechanistic insight into how C-C motif chemokine ligand 2 (CCL2) is upregulated in renal tubular epithelial cells (TECs) and contributes to kidney dysfunction during sepsis. The data reveal that lipopolysaccharide induces CCL2 expression through the Toll-like receptor 2/NF-κB signaling pathway in TECs. Endogenous CCL2 released from TECs, not from myeloid cells, is responsible for sepsis-induced kidney inflammation and acute kidney injury.