The small heat shock protein HSPB5 attenuates the severity of lupus nephritis in lupus-prone mice

Abstract

Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. The current treatments for LN are accompanied with severe immunotoxicity and have limits of effectiveness. Since our in vitro experiments demonstrated that a small heat shock protein (HSP), alpha-B crystallin (HSPB5; CRYAB), selectively modulates myeloid cells towards anti-inflammatory and tolerogenic phenotypes, the aim of this study was to investigate whether HSPB5 can attenuate the severity of LN. MRL/lpr mice were treated intravenously with HSPB5 at 2.5 or 10 μg/dose twice per week after disease onset, from 11 to 21 weeks of age. Disease progression was monitored by weekly measurements of proteinuria, and sera, spleens, and kidneys were collected for assessment at the terminal time point. Treatment with 10 μg HSPB5 substantially reduced endocapillary proliferation and tubular atrophy, which significantly reduced proteinuria and blood urea nitrogen (BUN). Compared to vehicle, 10 μg HSPB5 treatment substantially decreased activation/proliferation of splenocytes, increased IL-10+ macrophages, T and B regulatory cells (Treg, Breg), increased serum IL-10, and lowered expression of IL-6 in kidneys, which correlated with improved kidney function and pathology. This study demonstrated the utility of exogenous human HSPB5 to attenuate severe nephropathy in MRL/lpr mice and provides evidence in favour of a novel therapeutic approach for lupus nephritis.

Keywords:

• Heat shock protein
• HSPB5
• autoimmune
• lupus nephritis
• inflammation
• MRL/lpr
• drug development

Acknowledgements

The authors thank Drs. Jim Johnston, Tracy McGaha, Johannes M. van Noort, and James Campbell for helpful manuscript discussions.

Disclosure statement

SB, JK, MB and CS report personal fees from Serenity Bioworks.