TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice.
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.
Kelly
Fiona M
FM
Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Reddy
Ramesh N
RN
Roberts
Brian R
BR
Gangappa
Shivaprakash
S
Williams
Ifor R
IR
Gooch
Jennifer L
JL
D000375:Aging / Q000502:physiology; D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D006579:Heterozygote; D007668:Kidney / Q000503:physiopathology*; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008221:Lymphoid Tissue / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D019703:Calcineurin