Interleukin-13 Receptor α1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus Pathogenesis

Objective Age-associated/autoimmune B cells (ABCs) are an emerging B cell subset with aberrant expansion in systemic lupus erythematosus. ABC generation and differentiation exhibit marked sexual dimorphism, and Toll-like receptor 7 (TLR-7) engagement is a key contributor to these sex differences. ABC generation is also controlled by interleukin-21 (IL-21) and its interplay with interferon-gamma and IL-4. This study was undertaken to investigate whether IL-13 receptor alpha 1 (IL-13R alpha 1), an X-linked receptor that transmits IL-4/IL-13 signals, regulates ABCs and lupus pathogenesis. Methods Mice lacking DEF-6 and switch-associated protein 70 (double-knockout [DKO]), which preferentially develop lupus in females, were crossed with IL-13R alpha 1-knockout mice. IL-13R alpha 1-knockout male mice were also crossed with Y chromosome autoimmune accelerator (Yaa) DKO mice, which overexpress TLR-7 and develop severe disease. ABCs were assessed using flow cytometry and RNA-Seq. Lupus pathogenesis was evaluated using serologic and histologic analyses. Results ABCs expressed higher levels of IL-13R alpha 1 than follicular B cells. The absence of IL-13R alpha 1 in either DKO female mice or Yaa DKO male mice decreased the accumulation of ABCs, the differentiation of ABCs into plasmablasts, and autoantibody production. Lack of IL-13R alpha 1 also prolonged survival and delayed the development of tissue inflammation. IL-13R alpha 1 deficiency diminished in vitro generation of ABCs, an effect that, surprisingly, could be observed in response to IL-21 alone. RNA-Seq revealed that ABCs lacking IL-13R alpha 1 down-regulated some histologic characteristics of B cells but up-regulated myeloid markers and proinflammatory mediators. Conclusion Our findings indicate a novel role for IL-13R alpha 1 in controlling ABC generation and differentiation, suggesting that IL-13R alpha 1 contributes to these effects by regulating a subset of IL-21-mediated signaling events. These results also suggest that X-linked genes besides TLR7 participate in the regulation of ABCs in lupus.

Automated summary

The study revealed that IL-13R alpha 1 plays a crucial role in controlling the generation and differentiation of ABCs. Deficiency of IL-13R alpha 1 reduced the accumulation of ABCs, differentiation into plasmablasts, and autoantibody production, leading to prolonged survival and delayed tissue inflammation.