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Proteomic Signatures of Monocytes in Hereditary Recurrent Fevers.

ABSTRACT: Hereditary periodic recurrent fevers (HRF) are monogenic autoinflammatory associated to mutations of some genes, such as diseases caused by mutations of including MEFV, TNFRSF1A and MVK genes. Despite the identification of the causative genes, the intracellular implications related to each gene variant are still largely unknown. A large -scale proteomic analysis on monocytes of these patients is aimed to identify with an unbiased approach the mean proteins and molecular interaction networks involved in the pathogenesis of these conditions. Monocytes from HRF 15 patients (5 with MFV, 5 TNFRSF1A and 5with MVK gene mutation) and 15 healthy donors (HDs) were analyzed by liquid chromatography and tandem mass spectrometry before and after lipopolysaccharide (LPS) stimulation. Significant proteins were analyzed through a Cytoscape analysis using the ClueGo app to identify molecular interaction networks. Protein networks for each HRF were performed through a STRING database analysis integrated with a DISEAE database query. About 5000 proteins for each HRF were identified. LPS treatment maximizes differences between up-regulated proteins in monocytes of HRF patients and HDs, independently from the disease's activity and ongoing treatments. Proteins significantly modulated in monocytes of the different HRF allowed creating a disease-specific proteomic signatures and interactive protein network. Proteomic analysis is able to dissect the different intracellular pathways involved in the inflammatory response of circulating monocytes in HRF patients. The present data may help to identify a "monocyte proteomic signature" for each condition and unravel new possible unexplored intracellular pathways possibly involved in their pathogenesis. These data will be also useful to identify possible differences and similarities between the different HRFs and some multifactorial recurrent fevers.

SUBMITTER: Penco F

PROVIDER: S-EPMC9260596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hereditary recurrent fevers (HRF) are a group of monogenic autoinflammatory diseases characterized by auto-resolving attacks of sterile inflammation caused by mutations of MEFV, TNFRSF1A and MVK genes1-3. Familial Mediterranean fever (FMF) is the prototype of a HPR and is caused by gain-of-function mutations of the MEFV gene, coding for pyrin4 5. Pyrin is part of the Pyrin-Inflammasome that controls the activation and secretion of interleukin (IL)-1β and can be activated by the cortical actin cytoskeleton remodeling induced by bacterial toxins via RhoA. Mevalonate kinase deficiency (MKD) is secondary to bi-allelic mutations of the gene coding for mevalonate kinase (MVK), an enzyme involved in the cholesterol biosynthesis. Loss-of-function MVK mutations lead to a defective sterol synthesis and to a reduced prenylation of small G proteins, such as RhoA, favoring the activation of the Pyrin-inflammasome6-8. TNF receptor-associated periodic syndrome (TRAPS) is secondary to autosomal dominant mutations of the gene coding for the type I receptor for TNF (TNFRSF1A), resulting in a heap of misfolded TNF receptor 1 in the endoplasmic reticulum, leading to oxidative stress, defective autophagy and consequent over-secretion of pro-inflammatory cytokines9 10. The clinical manifestations of HRFs are rather unspecific and consist mainly in fever, serositis, skin rash, limb and articular pain. No specific biomarkers able to distinguish one among the different HRFs have been identified, so far11. Moreover, the majority of the studies investigating the pathogenic consequences of the genes’ mutations associated with the three HRFs were focused on the few mechanisms classically associated to the pro-inflammatory activation of cells of the innate immunity (NF-kB and MAPK activation, IL-1b activation and secretion). Conversely, an unbiased analysis of possible additional intracellular pathways involved in the different conditions has not been exploited. Recently, large-scale proteomics based on high-resolution mass spectrometry (MS) has offered a systems-wide hypothesis-free method to analyze intracellular pathways in order to identify new disease biomarkers12-14. Here, we analyzed the proteomic signature of unstimulated and stimulated monocytes of patients with FMF, TRAPS and MKD, describing the dysregulated intracellular pathways associated with each condition for the identification of possible biomarkers and possible novel therapeutic targets.

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Proteomic Signatures of Monocytes in Hereditary Recurrent Fevers.

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