Background/Purpose: Type I interferons and their mRNA signatures have become prominent in biomarkers of autoimmune and autoinflammatory disease activity. Two master regulators of type I interferon have emerged: interferon regulatory factor (IRF) 3 and 7. These transcription factors are differentially expressed in immune cells. Prior studies using the K/BxN serum transfer model demonstrated that the Irf7^-/- mice had increased swelling and the Irf3^-/- mice had reduced swelling compared to their C57BL/6 WT counterparts. Here we used the collagen induced arthritis (CIA) model to examine the roles of IRF3 and IRF7 in developing arthritis in a model dependent on the adaptive immune system.

Methods: Irf7^-/- and Irf3^-/- mice were backcrossed on to the DBA/1J background. To induce arthritis we gave an initial immunization sc with 100mg bovine type II collagen (bCII) in complete Freund’s adjuvant with 5mg/mL mycobacterial extract (Chondrex) and then a boost on day 21 with bCII in IFA. In confirmatory experiments bCII was injected in CFA with 2mg/ml M. Tb extract and then to synchronize arthritis 5mg of lipopolysaccharide was injected on day 28. Hind paws prepared for histology or microCT on Day 35 or 40. Sera tested by ELISA for IL-6 and anti-mouse collagen antibodies. Synovial tissues were frozen and mRNA harvested and qPCR performed.

Results: In the CIA model, DBA.Irf7 mice had greater ankle swelling (P<0.0001; F (2, 2095) = 27.51), than DBA.irf3 and WT mice, and DBA.Irf3 mice had with lower clinical scores (P<0.0001; F (2, 1302) = 35.85). There was no difference anti-mouse collagen type II (mCII) antibody levels or serum IL-6 between the groups. Strikingly there was minimal inflammation, bone erosion and cartilage damage in the DBA.Irf3 compared to the other groups (P=0.036; F (2, 27) = 3.978). In a second protocol adapted to increase arthritis severity using an injection of LPS on day 28. Using this protocol DBA.Irf3 (p<0.0001; F (1, 962) = 24.33) and DBA.Irf7 (P<0.001, F (1, 731) = 99.74) mice had decreased joint scores compared to WT DBA mice. DBA.Irf3 and DBA.Irf7 mice had the same levels of anti-mCII antibodies as WT. In the DBA.Irf3 male mice there was no significant difference in the cortical bone fraction (% BA/TA; 68.05±2.56 vs. 70.05±0.30, p>0.05) compared to WT, but there was a significantly lower trabecular bone volume fraction than WT as assessed by microCT (% BV/TV; 15.72±1.24 vs. 29.82±1.37; p<0.05). Joint extracts were prepared and gene expression was determined by qPCR. Interferon ß and associated transcripts (Cxcl10, Ccl5) were reduced in the synovial tissues DBA.Irf3, but not the DBA.Irf7 mice (p < 0.05). Mmp3, Mmp9, Mmp13, Rank and Opg mRNA were increased in the DBA.Irf3 mice and Cathepsin K mRNA was decreased. There was no significant difference in RANKL.

Conclusion: IRF7 deficiency had an impact on swelling but minimal impact on histologic bone damage in the CIA model. In contrast IRF3 deficiency was markedly protective of bone erosion and was associated with a decline in IFNß and cathepsin K mRNA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ifn-regulatory-factor-3-but-not-ifn-regulatory-factor-7-contributes-to-bone-erosion-in-collagen-induced-arthritis/