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TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha
Fiona M Kelly1, Ramesh N Reddy, Brian R Roberts
1Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Abstract:
Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the alpha isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAalpha(+/-)) mice. In addition to renal dysfunction and inflammation, we find that CnAalpha(+/-) mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-beta is significantly increased in CnAalpha(+/-) mice. Neutralization of TGF-beta attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAalpha causes uregulation of TGF-beta which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-beta may be a novel therapeutic target.
Insights
Haploinsufficiency of calcineurin alpha (CnAalpha) in mice leads to kidney dysfunction and the formation of tertiary lymphoid organs (TLOs). Increased transforming growth factor-beta (TGF-beta) drives TLO formation and kidney damage, suggesting TGF-beta as a therapeutic target.
Area of Science:
- Immunology
- Nephrology
- Molecular Biology
Background:
- Calcineurin is a key intracellular signaling molecule, and its inhibition by cyclosporin causes immunosuppression and nephrotoxicity.
- Previous studies showed homozygous loss of calcineurin alpha (CnAalpha) impairs kidney development, but early lethality limited further investigation.
- Cyclosporin-induced nephrotoxicity shares features with impaired kidney development, suggesting a role for calcineurin in renal health.
Purpose of the Study:
- To investigate the effects of heterozygous calcineurin alpha (CnAalpha(+/-)) deficiency on kidney function and development in aged mice.
- To determine the potential role of tertiary lymphoid organs (TLOs) in CnAalpha(+/-) mediated nephrotoxicity.
- To explore the involvement of transforming growth factor-beta (TGF-beta) in the pathogenesis of CnAalpha haploinsufficiency.
Main Methods:
- Analysis of aged heterozygous CnAalpha(+/-) mice exhibiting renal dysfunction and inflammation.
- Histopathological examination to identify and characterize lymphoid aggregates (TLOs) in kidneys and other organs.
- Measurement of TGF-beta levels and assessment of TGF-beta neutralization effects on TLO formation and kidney function.
Main Results:
- CnAalpha(+/-) mice developed spontaneous TLOs in multiple organs, including the kidney, small intestine, liver, and lung.
- Kidney function impairment was significantly correlated with TLO formation, suggesting a contribution to nephrotoxicity.
- Elevated TGF-beta levels were observed in CnAalpha(+/-) mice; TGF-beta neutralization attenuated TLO formation and improved kidney function.
Conclusions:
- Haploinsufficiency of CnAalpha leads to increased TGF-beta, chronic inflammation, and the formation of TLOs.
- TLO formation is linked to kidney dysfunction in CnAalpha(+/-) mice, potentially contributing to nephrotoxicity.
- This study suggests calcineurin inhibition may induce TLO formation and highlights TGF-beta as a potential therapeutic target for related conditions.
