Brief Report: Arthritis in KRN T Cell Receptor–Transgenic Mice Does Not Require Interleukin‐17 or Th17 Cells

Abstract

Objective Th17 cells and interleukin (IL)-17 cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies of mouse models of inflammatory arthritis have demonstrated a key role for the pro-inflammatory cytokine IL-17A and its receptor, the IL-17 receptor (IL-17R) A/C heterodimer. Using a rigorous genetic approach, we evaluated the contribution of Th17 cells and IL-17 in the autoantibody-dependent, KRN T cell receptor (TCR) transgenic mouse model of arthritis. Methods We bred KRN mice expressing the MHCII molecule Ag7 (K/B/g7) and genetically lacking the related cytokines IL-17A and IL-17F or their critical receptor subunit, IL-17RA. Using bone marrow transplantation, we generated mice in which K/B/g7 hematopoietic donor cells lacked the key Th17-differentiating transcription factor, Rorγt. Results K/B/g7 mice lacking both IL-17A and IL-17F produced normal titers of pathogenic autoantibodies and developed arthritis normally. Similarly, IL-17RA was not required for disease development in this model, nor was Rorγt expression by hematopoietic cells. Conclusions Despite prior reports suggesting that Th17 cells and IL-17A are crucially involved in the pathogenesis of arthritis in K/BxN mice, the results presented here provide genetic evidence that IL-17A and IL-17F, IL-17RA, and hematopoietic cell Rorγt expression are dispensable for normal arthritis progression in the K/B/g7 model system. We discuss potential explanations for the discrepancies between these two highly similar model systems. These findings plus those from other mouse models of arthritis provide insight regarding why biologic therapeutics targeting the Th17/IL-17 axis are beneficial in some human rheumatic diseases but not others.

Dual neutralisation of IL-17F and IL-17A with bimekizumab blocks inflammation-driven osteogenic differentiation of human periosteal cells

“…Furthermore, Ono et al clearly demonstrate that while IL-17A stimulates osteoblastogenesis of precursor cells from long bone repair tissue, it does the opposite in calvarial osteoblasts. 5 It is surprising that arthritis symptoms were not modulated in the study by Shaw et al , 14 as it has previously been reported that genetic IL-17A deficiency 17 or IL-17A antibody-mediated neutralisation 18 suppresses arthritic disease in the same model. This aspect was not discussed by the authors but does warrant further investigation.…”

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

“…Tfh17 cells are also expanded in KBN mice under the control of the microbiome ( 26 ). Recent studies have shown that Th17 cells are dispensable for the development of disease ( 27 ) and that the gut microbiome regulates KBN Tfh but not Th17 cells ( 28 ). Moreover, the analysis of K/BxN IL-21-VFP.IL-17A-GFP mice directly showed a robust expansion of IL-21-producing CD4 + T cells but very few IL-17-procuding CD4 + T cells (Roopenian, unpublished).…”

Editorial: Of Mice and Mice: Understanding Conflicting Murine Experimental Data

“…For example, an influential study by Wu et al published in 2010 demonstrated that the generation of arthritogenic antibodies in the K/BxN mouse model of arthritis was mediated by Th17 cells, and that these cells were in turn dependent on colonization with segmented filamentous bacteria (SFB), a commensal inhabitant of the mouse terminal ileum. In contrast, in this issue of Arthritis & Rheumatology , Auger et al report that interleukin‐17A (IL‐17A) is not required for the formation of arthritogenic antibodies in this model, and neither are SFB. Similar findings showing that IL‐17A was “dispensable” for K/BxN mouse arthritis were reported by other investigators .…”