Nucleosomes contribute to increase mesangial cell chemokine expression during the development of lupus nephritis

- Nucleosomes activate mesangial cells to produce chemokines.
- The chemokine produced by mesangial cells attracts effector cells and lymphocytes.
- Mesangial matrix ICs deposition increase chemokine production in (NZBxNZW)F1 mice.

Nucleosomes represent a set of major autoantigens in the induction of systemic lupus erythematosus (SLE), and appear to be essential for the development of lupus nephritis. Deposition of nucleosome-containing immune complexes within the mesangial matrix and activation of mesangial cells may be important in the progression of lupus nephritis from a “sleeping” minimal change disease state to a full blown disease state. This study investigated the renal cytokine profile both in vivo during the development of the disease in (NZBxNZW)F1 (B/W) mice, and in vitro in primary B/W mesangial cells stimulated with nucleosomes, nucleosome-IgG complexes, and anti-dsDNA mAb respectively. Nucleosomes alone stimulated primary mesangial cells in a dose dependent manner. Of the chemokines produced by activated mesangial cells, CCL2, CCL7, CCL20, CXCL1, CXCL2 and CXCL5 were highly up-regulated compared to unstimulated cells. These chemokines were also increased in vivo in anti-dsDNA antibody positive and nephritic B/W kidneys, and was accompanied by infiltration of neutrophils, macrophages, T and B cells. This study provides a link between nucleosome-containing immune complexes, activation of mesangial cells, infiltration of effector cells and the development of lupus nephritis. Nucleosomes are pro-inflammatory and trigger innate immune responses, and thus are not only passive targets for autoantibodies but may play an active role in lupus pathogenesis. The removal or increased enzymatic destruction of nucleosomes, and/or the inhibition of mesangial cell activation may be possible treatment strategies in lupus nephritis.