Activation of the NLRP3 inflammasome contributes to the pathogenesis of lupus nephritis, a serious manifestation of systemic lupus erythematosus (SLE). A new study reveals how the oncogene serine/threonine-protein kinase PIM1 interacts with the NLRP3 inflammasome to contribute to kidney damage in SLE.

Credit: Susanne Harris/Springer Nature Limited

PIM1 is known to modulate regulatory T cell differentiation and B cell survival, both of which are involved in the pathogenesis of SLE. PIM1 is also known to enhance the activity of the transcription factor NFATc1, which is the target of calcineurin inhibitors, drugs used to treat lupus nephritis. However, little is known about how PIM1 interacts with the NLRP3 inflammasome.

To investigate the role of PIM1 in lupus nephritis, the researchers used two different types of lupus-prone mice. Inhibition of PIM1 using AZD1208 reduced proteinuria and the severity of glomerulonephritis in NZB/W F1 mice compared with untreated mice, results that were recapitulated in MRL/lpr mice treated with the PIM1 inhibitor SMI-4a. PIM1 inhibition also reduced the expression of NFATc1, NLRP3 and caspase-1 in the kidneys of NZB/W F1 mice compared with untreated mice.

In vitro studies using human podocytes revealed that small interfering RNA inhibition of PIM1 reduced autoantibody-induced expression of NFATc1 and activation of the NLRP3 inflammasome. Interestingly, PIM1 inhibition stopped the increase in intracellular calcium concentrations caused by autoantibody stimulation. Calcium is a known activator of inflammasome signalling, suggesting that PIM1 might regulate NLRP3 inflammasome activation by controlling calcium flux.

Inhibition of PIM1 using AZD1208 reduced proteinuria and the severity of glomerulonephritis

“PIM1 participates in the pathogenesis of lupus nephritis by regulating both the NLRP3 inflammasome and NFATc1,” comments corresponding author Jijun Zhao. “Theoretically, PIM1 inhibitors might be superior to calcineurin inhibitors in lupus nephritis as they can inhibit both NLRP3 and NFATc1. However, further studies are needed to answer this question.”