α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses.

INTRODUCTION

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2-antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses.

METHODS

We investigated the roles of α2AP in the pathogenesis of LN using a pristane-induced lupus mouse model.

RESULTS

The levels of plasmin-α2AP complex and α2AP were elevated in the lupus model mice. In addition, α2AP deficiency attenuated the pristane-induced glomerular cell proliferation, mesangial matrix expansion, collagen production, fibrin deposition, immunoglobulin G deposition, and proinflammatory cytokine production in the model mice. We also showed that interferon-γ (IFN-γ), which is an essential inducer of LN, induced α2AP production through the c-Jun N-terminal kinase (JNK) pathway in fibroblasts. In addition, plasmin attenuated the IFN-γ-induced proinflammatory cytokine production through the AMPK pathway in macrophages, and α2AP eliminated these effects. Furthermore, we showed that α2AP induced proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages.

CONCLUSION

α2AP regulates the inflammatory responses through plasmin inhibition and proinflammatory cytokine production and is associated with the development of LN. Our findings may be used to develop a novel therapeutic approach for SLE.