Lipocalin-2 Exacerbates Lupus Nephritis by Promoting Th1 Cell Differentiation

Significance Statement Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN), but its exact role and the underlying mechanism of its association with the condition remain unclear. LCN2 is a key regulator of T helper type 1 (Th1) cell differentiation in the pathogenesis of LN, acting through the IL-12/signal transducer and activator of transcription 4 pathway in an autocrine or paracrine manner. Amelioration of nephritis in MRL/ lpr mice given LCN2-neutralizing antibodies and in pristane-treated LCN2 −/− mice, provides the first proof of concept that decreasing LCN2 protects against renal injury through dampening the Th1 response. LCN2 blockade may present a promising new strategy to attenuate LN. Background Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. Methods The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/ lpr mice and analyzing pristane-treated LCN2 −/− mice. Results LCN2 is highly expressed in CD4 + T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN- γ overexpression in CD4 + T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/ lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. Conclusions LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.