Inflammatory and Cell Death Signalling in Diabetes

Research Interests

The laboratory takes advantage of cell biological, genomic, and proteomic approaches to identify and characterise the mechanisms leading to inflammation-mediated dysfunction and death of insulin-producing β-cells in diabetes. A/Prof Cardozo was a pioneer in performing transcriptome profiling in primary β cells. Her studies demonstrated that β cells are not passive bystanders of their own destruction, but they promote an active “dialog” with immune-cells that contributes to islet inflammation and β-cell demise in type 1 diabetes. She has shown that activation of the transcription factor NF-κB is a crucial mediator of these β-cell pro-inflammatory and pro-apoptotic responses. She was the first to describe the role of NF-κB-induced endoplasmic reticulum stress in β-cells exposed to pro-inflammatory cytokines.

The Cardozo’s group has unveiled important crosstalks between endoplasmic reticulum stress and the mitochondrial apoptotic pathway leading to β-cell apoptosis, suggesting that endoplasmic reticulum stress may mediate pro-inflammatory responses in these cells. The main aim of her research is to devise novel treatments to prevent β-cell loss during diabetes. The current research topics of the Cardozo’s group are:

• Regulation of NF-κB activation and β-cell death in diabetes

• The role of endoplasmic reticulum stress in β-cell mediated pro-inflammatory and antiviral responses

• The crosstalk between endoplasmic reticulum stress and the mitochondrial apoptotic pathway contributing to β-cell demise

• The role of regulated necrosis in β-cell death in diabetes

Selected Publications

1. Lavis P, Morra S, Orte Cano C, Albayrak N, Corbière V, Olislagers V, Dauby N, Del Marmol V, Marchant A, Decaestecker C, Mascart F, De Vos N, Van de Borne P, Salmon I, Remmelink M, Parmentier M, Cardozo AK, Bondue B. Chemerin plasma levels are increased in COVID-19 patients and are an independent risk factor of mortality. Front Immunol 13:941663, 2022

2. Xiao P, Takiishi T, Violato NM, Licata G, Dotta F, Sebastiani G, Marselli L, Singh SP, Sze M, Van Loo G, Dejardin E, Gurzov EN, Cardozo AK.NF-κB-inducing kinase (NIK) is activated in pancreatic β-cells but does not contribute to the development of diabetes. Cell Death Dis 13(5):476, 2022

3. Tiezzi M, Morra S, Seminerio J, Van Muylem A, Godefroid A, Law-Weng-Sam N, Van Praet A, Corbière V, Orte Cano C, Karimi S, Del Marmol V, Bondue B, Benjelloun M, Lavis P, Mascart F, van de Borne P, Cardozo AK. SP-D and CC-16 Pneumoproteins' Kinetics and Their Predictive Role During SARS-CoV-2 Infection. Front Med (Lausanne) 8:761299, 2022.

4. Meyerovich K, Violato NM, Fukaya M, Dirix V, Pachera N, Marselli L, Marchetti P, Strasser A, Eizirik DL, Cardozo AK. MCL-1 is key anti-apoptotic protein in human and rodent pancreatic β-cells. Diabetes 66:2446-2458, 2017

5. Fukaya M, Brorsson CA, Catrysse L , Delaroche D, Vanzela EC, Meyerovich K, Ortis F, Beyaert R, Nielsen LB, Andersen ML, Mortensen HB, Pociot F, van Loo G, Størling J, Cardozo AK. TNFAIP3/A20 inhibits β-cell apoptosis by multiple mechanisms and predicts residual β-cell function in children newly-diagnosed for type 1 diabetes. Molecular Endocrinology 30:48-61, 2016

6. Meyerovich K, Fukaya M, Terra LF, Ortis F, Eizirik DL, Cardozo AK. The non-canonical NF-κB pathway is induced by cytokines in pancreatic β-cells and contributes to cell death and pro-inflammatory responses. Diabetologia 59:512-21, 2016

7. Allagnat F, Fukaya M, Nogueira TC, Welsh N, Marselli L, Marchetti P, Eizirik DL, Cardozo AK. C/EBP Homologous Protein (CHOP) Contributes to Cytokine-induced Pro-Inflammatory Responses and Apoptosis in Beta Cells. Cell Death Diff 19:1836-1846, 2012

8. Allagnat F, Cunha D, Moore F, Vanderwinden JM, Eizirik DL, Cardozo AK. Mcl-1 degradation by pro-inflammatory cytokines and palmitate is an early and major event for beta cell apoptosis. Cell Death Differ 18:328-37, 2011

9. Allagnat F, Christulia F, Ortis F, Pirot P, Lortz S, Lenzen S, Eizirik DL, Cardozo AK. Sustained expression of spliced XBP1 induces pancreatic beta-cell dysfunction and apoptosis. Diabetologia 53:1120-30, 2010 (Cover page of this issue)

10. Pirot P, Ortis F, Yanjun M, Hendershot L, Eizirik DL, Cardozo AK. Transcriptional regulation of the endoplasmic reticulum (ER) stress gene CHOP in pancreatic β-cells. Diabetes 56:1069-1077, 2007

11. Cardozo AK, Ortis F, Storling J, Feng Y-M, Rasschaert J, Tonnesen M, Van Eylen F, Mandrup-Poulsen T, Herchuelz A, Eizirik DL. Cytokines downregulate the sarcoendoplasmic-reticulum pump Ca2+-ATPase (SERCA)2b and deplete endoplasmic reticulum (ER)-Ca2+ leading to induction of ER-stress in pancreatic β-cells. Diabetes 54:452-461, 2005

12. Cardozo AK, Proost P, Gysemans C, Chen MC, Mathieu C, Eizirik DL. IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice. Diabetologia 46:255-266, 2003