The Role Played by Serine Proteases in the Development and Worsening of Vascular Complications in Type 1 Diabetes Mellitus

Finotti, Paola

doi:10.2174/157339906777950624

Cited by 9 publications

(6 citation statements)

References 128 publications

(198 reference statements)

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“…This group of proteins is characterized by the presence of a serine in the catalytic domain that is highly conserved between its members. Disorders of the dynamic balance of proteases and their inhibitors have been reported in the blood stream and in lymphocytes of diabetes patients and it has been proposed that increase of proteases concentrations represents an early marker of T1D [ 39 ]. Imbalance of the proteolytic system might also change the local homeostasis and interfere with the extracellular matrix of cells in the pancreas that become more permissive to lymphocyte invasion as it has been reported for tumour metastasis [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

Regnault

Fortéa²,

Miao³

et al. 2009

BMC Med Genomics

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BackgroundAutoimmune diabetes (T1D) onset is preceded by a long inflammatory process directed against the insulin-secreting β cells of the pancreas. Deciphering the early autoimmune mechanisms represents a challenge due to the absence of clinical signs at early disease stages. The aim of this study was to identify genes implicated in the early steps of the autoimmune process, prior to inflammation, in T1D. We have previously established that insulin autoantibodies (E-IAA) predict early diabetes onset delineating an early phenotypic check point (window 1) in disease pathogenesis. We used this sub-phenotype and applied differential gene expression analysis in the pancreatic lymph nodes (PLN) of 5 weeks old Non Obese Diabetic (NOD) mice differing solely upon the presence or absence of E-IAA. Analysis of gene expression profiles has the potential to provide a global understanding of the disease and to generate novel hypothesis concerning the initiation of the autoimmune process.MethodsAnimals have been screened weekly for the presence of E-IAA between 3 and 5 weeks of age. E-IAA positive or negative NOD mice at least twice were selected and RNAs isolated from the PLN were used for microarray analysis. Comparison of transcriptional profiles between positive and negative animals and functional annotations of the resulting differentially expressed genes, using software together with manual literature data mining, have been performed.ResultsThe expression of 165 genes was modulated between E-IAA positive and negative PLN. In particular, genes coding for insulin and for proteins known to be implicated in tissue remodelling and Th1 immunity have been found to be highly differentially expressed. Forty one genes showed over 5 fold differences between the two sets of samples and 30 code for extracellular proteins. This class of proteins represents potential diagnostic markers and drug targets for T1D.ConclusionOur data strongly suggest that the immune related mechanisms taking place at this early age in the PLN, correlate with homeostatic changes influencing tissue integrity of the adjacent pancreatic tissue. Functional analysis of the identified genes suggested that similar mechanisms might be operating during pre-inflammatory processes deployed in tissues i) hosting parasitic microorganisms and ii) experiencing unrestricted invasion by tumour cells.

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Section: Resultsmentioning

confidence: 99%

Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

Regnault

Fortéa²,

Miao³

et al. 2009

BMC Med Genomics

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“…It is known that growth factors and cytokines that stimulate the expression of MMP‐9 [17–19] also mutually affect the expression and cellular secretion of HSPs [9], the inflammatory response being thus activated and expanded by autocrine‐paracrine mechanisms [20, 21]. In particular, an increased expression of MMP‐9 has been shown to correlate positively with up‐regulation of HSP70 [22], an event known to occur in the process of capillary formation and maturation [23].…”

Section: Resultsmentioning

confidence: 99%

“…The unique immunomodulatory role played by Grp94 is further confirmed by the fact that, similarly to its cytoplasmic homologue HSP90 and to HSP70, Grp94 is capable of inducing intense inflammatory/immune reactions that ultimately lead to the development of autoimmune diseases [7, 8]. The additional finding that the level of Grp94 in the plasma of diabetic patients is apparently unrelated with the duration of diabetes and metabolic control [3, 4], raised the question of whether Grp94 in plasma may be a marker of disease associated with an increased risk of vascular inflammation [9]. To test this hypothesis, in this work we studied the effects of plasma‐purified Ab fractions, containing immune complexes with Grp94, on HUVECs, taken as a model of vascular cells.…”

Section: Introductionmentioning

confidence: 99%

Angiogenic transforming capacity of IgG purified from plasma of type 1 diabetic patients

Tramentozzi

Pagetta

Frasson

et al. 2009

J Cellular Molecular Medi

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We previously demonstrated that plasma of type 1 diabetic patients contains antibodies complexed irreversibly with Grp94 that also display proteolytic activity. In this work, we wanted to test whether antibodies obtained from diabetic plasma may convey an inflammatory risk on vascular cells. To this aim, IgG were purified on the Protein-G column from individual plasma of eight type 1 diabetic patients, and then tested on HUVECs to measure effects on cell growth and morphologic changes at different incubation times. The purified fractions of IgG contained a significant amount of Fab/(Fab)2, both free and in big aggregates, and anti-Grp94 antibodies, mostly irreversibly linked with, but also free of Grp94. The purified fractions of both Fab/(Fab)2 and whole IgG stimulated the proliferation and sustained the angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) at sub-nanomolar concentrations. IgG from normal plasma neither stimulated the cell growth nor induced any differentiation of HUVECs. The maximum cell growth stimulation occurred at 6–9 hrs and associated with the strong activation of the ERK1/2 pathway, whereas angiogenic transformation was completed later when the ERK1/2 activation was silenced and cell growth stimulation significantly reduced. Neither proteolytic activity of MMP-9 nor VEGF were apparently involved in mediating the angiogenic differentiation of HUVECs that mostly correlated with an increased expression of HSP70 closely coupled with cell membrane-bound inactive species of MMP-9. Results indicate that effects displayed on HUVECs by antibodies purified from diabetic plasma are likely sustained by immune complexes with Grp94 that may thus predict an increased risk of angiogenic transformation in vivo.

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“…Serine proteases (SPs) have been reported to be abnormally regulated in diverse chronic diseases 14,[56][57][58] . For example, during carcinogenic development SPs influence metastasis and cancer progression 59,60 , while in the context of diabetes they control fibrinolysis, coagulation and inflammation which in turn affects disease severity 57 . This led us to hypothesize that shared molecular mechanisms between some chronic diseases and COVID-19 could be explained in part by the regulation of SPINT2 .…”

Section: Discussionmentioning

confidence: 99%

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

Alvarez

Sharma

Kee

et al. 2020

Preprint

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COVID-19 outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 has been shown to be important for S protein priming and viral entry, however, little is known about its regulation. SPINT2 is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2. Here, we explored the existence of a co-regulation between SPINT2/TMPRSS2 and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 knockdown. Additionally, we evaluated the expression of SPINT2 in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors as well as in alpha pancreatic islets cells from diabetes Type 2 patients, which could have implications for the observed comorbidities in COVID-19 patients suffering from chronic diseases.

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The Role Played by Serine Proteases in the Development and Worsening of Vascular Complications in Type 1 Diabetes Mellitus

Cited by 9 publications

References 128 publications

Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

Angiogenic transforming capacity of IgG purified from plasma of type 1 diabetic patients

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

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