Sharon N Cox1, Grazia Serino1, Fabio Sallustio1, Antonella Blasi2, Michele Rossini1, Francesco Pesce3, Francesco Paolo Schena4. 1. Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. 2. Medestea Research and Production Laboratories, Consorzio CARSO, Bari, Italy. 3. Genomics of Common Disease, Imperial College, London, UK. 4. C.A.R.S.O. Consortium, Valenzano, Bari, Italy Research Center of Kidney Diseases, Schena Foundation, Valenzano, Bari, Italy.
Abstract
BACKGROUND: The main defect of immunoglobulin A nephropathy (IgAN) lies within the immune system and in peripheral blood mononuclear cells rather than in the kidney. Previously, we found an altered gene expression in monocytes compared with B and T cells isolated from IgAN patients; thus, our aim here has been to study this subset at a genome-wide and functional level. METHODS: A total of 39 IgAN patients and 37 healthy blood donors (HBDs) were included in this study, and microarray technology was used to evaluate global gene expression differences in monocytes isolated from IgAN patients and HBDs. Aberrantly expressed genes and pathways were then validated on an independent set of IgAN patients with RT-PCR western blot and flow cytometric analysis. RESULTS: Gene expression differences in monocytes from IgAN patients and HBDs primarily involved apoptosis signalling, mitochondrial dysfunction, tnfr2/1 and death receptor signalling. Both the extrinsic and intrinsic apoptotic pathways seem to be implicated; in particular, the protein levels of NDUFS3 and TNFRSF1A were upregulated thus confirming the altered mitochondrial and death receptor homeostasis. Furthermore, the basal intracellular protein levels of TNF in monocytes were lower in IgAN patients compared with HBDs. We validated at protein level an enhanced apoptotic phenotype and a different subset distribution in monocytes from IgAN patients. We found that the non-classical monocyte subset (CD14(+)CD16(+)) was significantly expanded in all IgAN patients tested even though the total monocyte count remained unchanged. CONCLUSIONS: Our findings demonstrate, for the first time, an aberrant modulation of the mitochondrial respiratory system in monocytes isolated from IgAN patients. Furthermore, the aberrant expansion of the (CD14(+)CD16(+)) subset could explain the enhanced apoptotic phenotype seen in these cells thus revealing their potential role in the pathogenesis of IgAN.
BACKGROUND: The main defect of immunoglobulin A nephropathy (IgAN) lies within the immune system and in peripheral blood mononuclear cells rather than in the kidney. Previously, we found an altered gene expression in monocytes compared with B and T cells isolated from IgANpatients; thus, our aim here has been to study this subset at a genome-wide and functional level. METHODS: A total of 39 IgANpatients and 37 healthy blood donors (HBDs) were included in this study, and microarray technology was used to evaluate global gene expression differences in monocytes isolated from IgANpatients and HBDs. Aberrantly expressed genes and pathways were then validated on an independent set of IgANpatients with RT-PCR western blot and flow cytometric analysis. RESULTS: Gene expression differences in monocytes from IgANpatients and HBDs primarily involved apoptosis signalling, mitochondrial dysfunction, tnfr2/1 and death receptor signalling. Both the extrinsic and intrinsic apoptotic pathways seem to be implicated; in particular, the protein levels of NDUFS3 and TNFRSF1A were upregulated thus confirming the altered mitochondrial and death receptor homeostasis. Furthermore, the basal intracellular protein levels of TNF in monocytes were lower in IgANpatients compared with HBDs. We validated at protein level an enhanced apoptotic phenotype and a different subset distribution in monocytes from IgANpatients. We found that the non-classical monocyte subset (CD14(+)CD16(+)) was significantly expanded in all IgANpatients tested even though the total monocyte count remained unchanged. CONCLUSIONS: Our findings demonstrate, for the first time, an aberrant modulation of the mitochondrial respiratory system in monocytes isolated from IgANpatients. Furthermore, the aberrant expansion of the (CD14(+)CD16(+)) subset could explain the enhanced apoptotic phenotype seen in these cells thus revealing their potential role in the pathogenesis of IgAN.
Authors: Senka Sendic; Ladan Mansouri; Sigrid Lundberg; Anna Nopp; Stefan H Jacobson; Joachim Lundahl Journal: PLoS One Date: 2021-03-19 Impact factor: 3.240
Authors: S N Cox; F Pesce; J S El-Sayed Moustafa; F Sallustio; G Serino; C Kkoufou; A Giampetruzzi; N Ancona; M Falchi; F P Schena Journal: J Intern Med Date: 2016-10-11 Impact factor: 8.989