Loss of interleukin-1 beta is not protective in the lupus-prone NZM2328 mouse model

Abstract

Aberrant activation of the innate immune system is a known driver of lupus pathogenesis. Inhibition of the inflammasome and its downstream signaling components in murine models of lupus has been shown to reduce the severity of disease. Interleukin-1 beta (IL-1β) is a proinflammatory cytokine released from cells following inflammasome activation. Here, we examine how loss of IL-1β affects disease severity in the lupus-prone NZM2328 mouse model. We observed a sex-biased increase in immune complex deposition in the kidneys of female mice in the absence of IL-1β that corresponds to worsened proteinuria. Loss of IL-1β did not result in changes in overall survival, anti-dsDNA autoantibody production, or renal immune cell infiltration. RNA-sequencing analysis identified upregulation of TNF and IL-17 signaling pathways specifically in females lacking IL-1β. Increases in these signaling pathways were also found in female patients with lupus nephritis, suggesting clinical relevance for upregulation of these pathways. Together, these data suggest that inhibition of the inflammasome or its downstream elements that block IL-1β signaling may need to be approached with caution in SLE, especially in patients with renal involvement to prevent potential disease exacerbation.

Assessment of the role of high-density lipoproteins and their immunomodulatory activity in systemic lupus erythematosus immunopathology

“…As expected, individuals with SLE carry an inflammatory burden that is partly mediated by proinflammatory cytokines; the levels of the cytokines IL-6 and IL-18 are usually increased in these patients and are correlated with disease activity, 21 22 yet the serum IL-1β level in patients with SLE is still unclear. 23 We measured the cytokine levels in the serum and found that the levels of both cytokines were significantly greater in the SLE population (p<0.0001, figure 2A, C , online supplemental table S2 ). We also observed that the increased levels of both IL-6 and IL-1β were not significantly different between patients with active and remission SLE ( figure 2B, D ).…”

The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice

“…Notably, experimental studies utilizing lupus models have provided compelling evidence supporting the link between increased expression of IL-1β and the severity and accelerated progression of the disease 66 , 67 . IL-1β knockout in lupus-prone NZM2328 mice still leads to the development of lupus phenotypes 68 . This finding suggested that the other signaling pathway is required for lupus development in NZM2328 mice.…”

B cell–intrinsic Myd88 regulates disease progression in murine lupus

“…Myd88 −/− MRL.Fas lpr mice have markedly reduced autoimmunity with ameliorated nephritis and dermatitis, loss of autoantibody production, and dampened immune activation ( Nickerson et al, 2010 ; Sadanaga et al, 2007 ). Furthermore, mice with deletion of both the TLR7 and TLR9 alleles recapitulated the majority of the Myd88 −/− MRL.Fas lpr phenotype, which suggests that MyD88 potentiation of disease resides downstream of these two endosomal TLRs ( Nickerson et al, 2010 ) and is independent of IL-1 signaling ( Loftus et al, 2023 ).…”