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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Zhu Chen - , Southern University of Science and Technology (Author)
  • Danny Flores Castro - , Hospital for Special Surgery (HSS) (Author)
  • Sanjay Gupta - , Hospital for Special Surgery (HSS) (Author)
  • Swati Phalke - , Hospital for Special Surgery (HSS) (Author)
  • Michela Manni - , Hospital for Special Surgery (HSS) (Author)
  • Juan Rivera-Correa - , Hospital for Special Surgery (HSS) (Author)
  • Rolf Jessberger - , Institute of Physiological Chemistry, TUD Dresden University of Technology (Author)
  • Habib Zaghouani - , University of Missouri (Author)
  • Eugenia Giannopoulou - , Hospital for Special Surgery (HSS), City University of New York (Author)
  • Tania Pannellini - , Hospital for Special Surgery (HSS) (Author)
  • Alessandra B Pernis - , Hospital for Special Surgery (HSS), Weill Cornell Medical College (Author)

Abstract

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-γ and IL-4. This study was undertaken to investigate whether IL-13 receptor α1 (IL-13Rα1), 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-13Rα1-knockout mice. IL-13Rα1-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-13Rα1 than follicular B cells. The absence of IL-13Rα1 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-13Rα1 also prolonged survival and delayed the development of tissue inflammation. IL-13Rα1 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-13Rα1 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-13Rα1 in controlling ABC generation and differentiation, suggesting that IL-13Rα1 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.

Details

Original languageEnglish
Pages (from-to)1544-1555
Number of pages12
JournalArthritis and Rheumatology
Volume74
Issue number9
Publication statusPublished - Sept 2022
Peer-reviewedYes

External IDs

PubMedCentral PMC9427689
Scopus 85136830253

Keywords

Keywords

  • Animals, Female, Interleukin-13/metabolism, Interleukin-13 Receptor alpha1 Subunit/genetics, Interleukin-4, Lupus Erythematosus, Systemic/genetics, Male, Mice, Mice, Knockout, Receptors, Interleukin-13/genetics, Toll-Like Receptor 7

Library keywords