Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40-60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus-prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus-prone mouse models, we showed the pathogenic role of a kidney-infiltrating CD11c myeloid cell population in LN. These CD11c cells accumulated in the kidneys of lupus-prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C) mature monocytes. The cytokine/chemokine profile of these renal-infiltrating CD11c cells suggests their roles in promoting LN, which was confirmed further in a loss-of-function in-vivo study by using an antibody-drug conjugate (ADC) strategy targeting CX CR1, a chemokine receptor expressed highly on these CD11c cells. However, CX CR1 was dispensable for the homing of CD11c cells into lupus nephritic kidneys. Finally, we found that these CD11c cells co-localized with infiltrating T cells in the kidney. Using an ex- vivo co-culture system, we showed that renal-infiltrating CD11c cells promoted the survival, proliferation and interferon-γ production of renal-infiltrating CD4 T cells, suggesting a T cell-dependent mechanism by which these CD11c cells promote LN. Together, our results identify a pathogenic kidney-infiltrating CD11c cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN.

Lupus nephritis, a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), manifests as inflammatory infiltration of the kidney. Many types of leukocytes infiltrate the kidney during the progression of lupus nephritis, but the specific contributions of each infiltrating population are still unclear. In this study, we have found that CD11c+cells accumulate in nephritic kidneys of lupus-prone mice. These renal CD11c+ cells, forming clusters with infiltrating T cells, are proinflammatory and secreting cytokines that promote autoantibody production and Th17 response. They also produce chemokines that attract other leukocytes into the kidney. The surface phenotype (CD11b+CD115highCD135lowCX3CR1highFcgRIVhigh)suggests that they may be derived from mature monocytes and be activated by pathogenic immune complexes. Ex vivo co-culture experiments also suggest that they can maintain the survival of renal infiltrating T cells. To further demonstrate the role of these CD11c+ cells in vivo, we are currently depleting them by targeting CX3CR1, as they are a unique population of cells predominantly expressing a high level of CX3CR1. The results obtained from this study will be important for the understanding of lupus pathogenesis and identification of new therapeutic targets against lupus nephritis.