Background/Purpose: Systemic lupus erythematosus is an autoimmune disease with pleotropic manifestations, including severe skin disease, hematologic abnormalities and nephritis.  Clinically, lupus is characterized by episodes of flare and remission, and exposures such as UV light or viral infections have been proposed as flare triggers.  However, induction of flare has been difficult to emulate in murine models. Here, we describe a system in which cutaneous injury is able to trigger the development of a lupus nephritis flare in lupus-prone mice.

Methods: 20-week old NZM2328 (NZM) female mice were depilated in a 2×4 cm area on the dorsal skin followed by 25 applications of duct tape under isofluroane anesthesia.  NZM mice lacking the type I interferon (IFN) receptor (iNZM) were used as a non-lupus prone control.  Skin biopsies were taken prior to and following tape-stripping, and gene expression changes were evaluated via quantitative PCR.  Serial blood draws and urine collection were obtained following tape stripping, and anti-double-stranded DNA titers, C3 levels and urine albumin/creatinine ratios were measured via commercially available kits.  Inflammatory cells were isolated from whole kidneys and cell populations were measured via flow cytometry.  Renal immune complex deposition was assessed via immunofluorescent staining for IgG and C3.  Renal inflammation was assessed on Hematoxylin and Eosin stained sections by a blinded renal pathologist.

Results:   NZM mice subjected to tape stripping had a rapid dermal upregulation of type I IFN-mediated and inflammatory gene expression.  Importantly, tape-stripped NZM mice developed onset of proteinuria and death within 3 weeks of skin injury whereas non-tape stripped littermates remained free of proteinuria. This was coupled with a drop in serum C3.  Proteinuria induction did not occur in tape-stripped iNZM mice, suggesting the rapid death was not secondary to skin injury itself. In NZM mice, renal immune complex deposition was enhanced within two weeks of tape stripping, as was renal expression of the B cell chemokine CXCL13.  Evaluation of renal inflammatory cell populations revealed an increased infiltrate of B cells in the kidney prior to proteinuria onset. 

Conclusion:   Cutaneous injury via tape-stripping induces a rapid flare of lupus nephritis that is preceded by enhanced renal immune complex deposition and B cell recruitment.  This novel model provides a mechanism to study the communication between the dermal and renal immune systems and how crosstalk between these systems can lead to lupus flare, thus providing potential targets for prevention of flares in human disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dermal-injury-promotes-nephritis-flare-in-lupus-prone-nzm2328-mice/