Heme-induced activation of the TLR3/TRIF-IFN-I-CCL2 pathway contributes to kidney injury in sickle cell disease.

Sickle cell nephropathy (SCN) is a major clinical complication in sickle cell disease (SCD), yet its underlying mechanisms remain incompletely defined. Hemolysis, a hallmark of SCD, has been implicated in SCN pathogenesis, but the downstream inflammatory pathways are not fully understood. We previously demonstrated that hemolysis triggers type I interferon (IFN-I) responses, leading to the upregulation of the C-C motif chemokine ligand 2 (CCL2) and recruitment of classical monocytes that differentiate into monocyte-derived macrophages (MoMϕ) within livers in SCD. In this study, we show that IFN-I and CCL2 levels are elevated in the plasma of patients with SCD with abnormal urine albumin-to-creatinine ratio and in the kidneys of the SCD Townes mouse model. Using IFN-I receptor (Ifnar1)-/- and CCL2 receptor (Ccr2)-/- mouse models of SCD, we demonstrate that the loss of IFN-I or CCL2 signaling reduces MoMϕ accumulation, renal inflammation, and renal injury. Mechanistically, we identify that hemin-induced IFN-I production occurs via the Toll-like receptor 3 (TLR3)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling axis, independent of MyD88, MAVS, or STING. These findings uncover a previously unrecognized heme-TLR3/TRIF-IFN-I-CCL2 pathway that contributes to renal pathology in SCD and suggest that targeting this axis may offer therapeutic benefit.