Background/Purpose:

The levels of IL-33, a Th2 promoting cytokine, and the soluble form of its receptor ST2 were reported to be elevated in serum of patients with active systemic lupus erythematosus (SLE), suggesting a role of the IL-33/ST2 axis in the pathogenesis of SLE. This study aims to examine the effect of IL-33 in disease severity of murine lupus.

Methods:

IL-33 was injected intraperitoneally 3 times per week to pre-diseased MRL/lpr mice aged 12 weeks for 6 weeks. Control group was given 1% BSA injection. Urine protein was monitored weekly by albustix and protein assay. Immunophenotyping of splenocytes was examined by flow cytometry. Splenic CD11b+ monocytic cells were isolated by microbeads for mRNA examination.

Results:

IL-33-treated mice (n=9) developed significantly less proteinuria compared to BSA-treated group (n=9). Kidney histology of the IL-33-treated group showed remarkably less mesangial deposit, diffuse proliferative glomerular changes and crescents, and had significantly lower renal composite score compared to controls (median 2.0 vs 9.9, p<0.001). Kidneys of these mice expressed lower mRNA levels of TNF-α (32.1+14.7 vs 77.0+27.8, p<0.001), IL-6 (median 0.6 vs 4.7, p=0.003), IL-1β (31.1+10.1 vs 77.8+24.6, p<0.001) and iNOS (p=0.006). Immunophenotyping of splenocytes showed significantly increased CD4+CD25+ regulatory T (Treg) cells (4.0+1.2% vs 2.2+0.2%, p<0.001) that expressed remarkably higher Foxp3 (76.0+5.0% vs 59.3+12.6%, p=0.002). Splenic extracts showed predominant Gata3 (0.37+0.20 vs 0.12+0.09, p=0.01) and Foxp3 (0.42+0.16 vs 0.17+0.11, p=0.002) mRNA in IL-33-treated mice. These Treg cells expressed high cell surface ST2 (8.9+2.7% vs 4.5+2.0%, p=0.008). There was significant expansion of splenic CD11b+ population in IL-33-treated mice (17.8+10.5 vs 8.8+3.0, p=0.01) that expressed significantly higher CD206 (5.2+0.9% vs 2.9+0.9%, p=0.002). Isolated splenic CD11b+ cells expressed significantly higher mRNA of Arg1, FIZZI and Ym-1 and IL-10 (all p=0.01) with reduced expression of iNOS (p=0.02). Kidney extracts of IL-33 treated mice also had elevated mRNA levels of M2 markers including Arg1 (median 199.8 vs 36.1, p=0.004) and FIZZI (median 25.0 vs 2.7, p<0.001) and reduced MCP-1 (12.7+6.5 vs 35.1+12.0, p<0.001). There was also significantly higher levels of mRNA of Foxp3 (median 43.0 vs 20.8, p=0.006) and Gata 3 (1.7+0.5 vs 0.9+0.5, p=0.008) but lower Rorc (2.6+1.0 vs 3.8+0.8, p=0.008) and Tbx21 (12.6+6.0 vs 29.6+13.7, p=0.003) in the kidneys.

Conclusion:

Exogenous IL-33 led to significantly less proteinuria and renal inflammation. These mice had significantly higher splenic Treg cells with prominent Foxp3 expression. Isolated CD11b+ cells from spleen and kidney extracts demonstrated mRNA levels of M2 macrophage polarisation.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-33-ameliorates-murine-lupus-via-induction-of-regulatory-t-cells-and-m2-macrophage-polarisation/