NOD Mice Exocrinopathy: Towards a Neuroimmune Link

Calafat, Mario Jose; Larocca, Luciana; Roca, Valeria Ines; Leirós, Claudia Pérez

doi:10.1159/000110643

Cited by 3 publications

(7 citation statements)

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“…Females in particular display a spontaneous Th1 autoimmune response against exocrine glands with a progressive loss of salivary secretion characteristic of Sjögren's syndrome [26] . Immune, nervous and endocrine factors seem to converge in the etiology of this autoimmune exocrinopathy that occurs before the onset of type I diabetes offering a suitable model to study such interactions at every disease stage [27] . Saravia's contribution [pp.…”

Section: Early Pregnancy and Autoimmune Diseases: Reciprocal Modulationmentioning

confidence: 99%

Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

Larocca

Ramhorst²,

Roca³

et al. 2008

Neuroimmunomodulation

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Neuroimmune-endocrine interactions seem to be central to the dialogue between the mother and the growing embryo during normal pregnancy. A proinflammatory Th1 microenvironment appears to be associated with embryo implantation but an excess of these cytokines may be deleterious. When normal gestation is subjected to stressful stimuli as those provided by a chronic inflammatory milieu, the activation profile of T cells and macrophages may be temporarily changed. Although much evidence supports the protective role of pregnancy in Th1 autoimmune diseases, the comprehension of the maternofetal interaction in an inflammatory context may serve to get more insight into pregnancy failures. Macrophages integrate multiple inputs and signals of neuroimmune-endocrine systems and they appear as major participants in either embryo implantation or loss. Changes at the macrophage level during gestation might help to understand their regulatory role in embryo implantation as well as to disclose their local and systemic pathogenic potential.

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Section: Early Pregnancy and Autoimmune Diseases: Reciprocal Modulationmentioning

confidence: 99%

Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

Larocca

Ramhorst²,

Roca³

et al. 2008

Neuroimmunomodulation

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“…In keeping with this, we have shown early signalling alterations in submandibular glands from NOD mice involving neural isoform of nitric oxide synthase (NOS 1), calcium-calmodulin kinase II and cGMP [ 11 , 12 ]. Moreover, with a lower activity of NOS 1 in exocrine glands and higher serum levels of TNF-α, we recently reported an increased DNA fragmentation with increased Bax expression in isolated acinar cells from NOD submandibular glands at the Sjögren's syndrome-like period [ 13 , 14 ]. TNF-α and TNF-α receptors (TNF-αR) are important cell surface inducers of apoptosis leading to proteolysis and DNA fragmentation [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Vasoactive intestinal peptide inhibits TNF-α-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands

et al. 2009

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IntroductionThe role of apoptotic secretory epithelium as a pro-inflammatory triggering factor of exocrine dysfunction is currently explored in Sjogren's syndrome patients and in the nonobese diabetic (NOD) mouse model. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects in various models of chronic inflammation. Our goal was to analyse the effect of TNF-α on apoptotic mediators in isolated acinar cells from NOD submandibular gland and their modulation by VIP.MethodsAcinar cells were isolated from submandibular glands of 16-week-old NOD females with salivary flow decline. Age-matched BALB/c females or eight-week-old NOD females were used as controls. Apoptotic mediators and TNF-α receptor expression were assessed by immunoblotting and RT-PCR, caspase 3 activity was assessed by optical density at 405 nm with Ac-DEVD-pNA as a substrate and chromatin condensation by Hoechst stain. They were evaluated in resting conditions and after a 3.5 or 6 hours of culture with TNF-α. VIP effects in acinar cells were assessed at 100 nM in TNF-α-treated cultures and VIP receptor functional assays by radio immunoassay (cAMP) or enzymatic detection (amylase).ResultsNOD acinar cells at 16 weeks present an increased expression of TNF-α receptor1 together with increased Bax, tumour protein 53-induced nuclear protein1α (TP53INP1α), caspase 3 activity and chromatin condensation. Acini from NOD mice were more sensitive to TNF-α-induced increases of apoptotic mediators than control cells. VIP inhibited TNF-α-induced apoptotic events through functional VPAC1 receptors coupled to the protein kinase A (PKA) signalling pathway.ConclusionsOur results indicate that acinar cells isolated from submandibular glands of NOD mice with salivary dysfunction are more sensitive to apoptosis induced by TNF-α which could be prevented by VIP through a PKA-mediated pathway.

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“…Previous reports indicate that VIP also prevents diabetes development in NOD mice 33 , 34 . The protective mechanism is associated with reduced circulating levels of Th1 cytokines, increased levels of IL‐10 and upregulation of markers for regulatory T cells 27 , 33 , 35 …”

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confidence: 96%

“…It decreases the Th1/Th2 cytokine ratio and promotes T regulatory functions 17 , 18 , 19 , 23 . An increasing body of in vivo data indicates that administration of VIP or pituitary adenylate cyclase‐activating peptide may have promising outcomes in the treatment of inflammatory and autoimmune diseases, in particular Th1‐associated pathologies such as multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome and Crohn's disease 24 , 25 , 26 , 27 , 28 . It has recently been described that VIP regulates both in vivo Th17 and IL‐17 production in autoimmunity, 29 , 30 and in vitro Th17 differentiation 31 , 32 .…”

mentioning

confidence: 99%

“…33,34 The protective mechanism is associated with reduced circulating levels of Th1 cytokines, increased levels of IL-10 and upregulation of markers for regulatory T cells. 27,33,35 As the equilibrium between different T-cell subsets is involved in the final outcome leading to tolerance or autoimmunity, the aim of the present work is to examine the evolution of T-cell marker functions during the development of autoimmune diabetes and the effect of VIP treatment, showing a time-course study of its effect on molecular and immunological mechanisms and analyzing the ratio of Th17/Tregs, Th17/Th1 or Th2/Th1 cells.…”

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New insights into the role of VIP on the ratio of T‐cell subsets during the development of autoimmune diabetes

et al. 2010

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Type I diabetes is an autoimmune T-cell-mediated disease associated with overexpression of inflammatory mediators and the disturbance of different T-cell subsets. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent with regulatory effects on activated T cells. As the equilibrium between different T-cell subsets is involved in the final outcome, leading to tolerance or autoimmunity, we studied the evolution of markers for T cells in nonobese diabetic (NOD) mice. The study of different transcription factors, cytokines or cytokine receptors, shows that VIP interferes with functional phase of T helper 17 (Th17) cells and prevents the increase in the proportion of Th1 to Th17 cells. On the other hand, VIP-treated NOD mice show an increase in the proportion of CD4 + CD25 + cells in the spleen. Thus, VIP switches the Tregs/Th17 ratio leading to tolerance in NOD mice. Similarly, VIP reverses the ratio of Th1-/Th2-cell subsets associated with autoimmune pathology. All these effects on the ratio of T-cell subsets and the anti-inflammatory effect of VIP in decreasing proinflammatory mediators result in a reduction of b-cell destruction in pancreas. Taken together, these results show that VIP provides significant protection against spontaneous diabetes by modulating T-cell subsets and counterbalancing tolerance and immunity. Keywords: vasoactive intestinal peptide; NOD mice; type I diabetes; Th17; T-cell subsets; regulatory T cell Human type I diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic insulin-producing b-cells. 1,2 The autoimmune response is believed to be due to a breakdown of immunological tolerance, resulting in a lack of immunoregulation of autoreactive diabetogenic T cells. The nonobese diabetic (NOD) mouse is a strain that is genetically prone to develop different, organspecific, autoimmune diseases. It has been a very useful model for studying the mechanisms involved in the initiation and propagation of T1D. 3 In NOD mice, islet antigens first appear in the pancreatic lymph nodes at around 2-4 weeks of age; autoreactive effectors T cells are sensitized and then infiltrate the islets. 4 Progression to overt disease occurs in 80% of female mice between 10 and 30 weeks and it results from T-cell-mediated islet destruction.T helper (Th) cells have been classified into different functional subsets, each characterized by its specific cytokine pattern and effector function. 5 The Th1 subset is thought to be a crucial player in most organ-specific autoimmunity, including T1D, in which type I cytokines (interferon-g (IFNg), interleukin-2 (IL-2) and tumor necrosis factor-a (TNFa)) predominate over type II (Th2) and regulatory (Tregs) cytokines (IL-4 and IL-10). Two important classes of Tregs within the CD4 + T-cell subset are CD4 + CD25 + Foxp3 + Tregs and T-regulatory type I (Tr1) cells, that differ in a number of biological features. There are two major categories of CD4 + CD25 + Foxp3 + Tregs, the naturally occurring CD4 + CD25 + Foxp3 + Tregs from the thymus...

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NOD Mice Exocrinopathy: Towards a Neuroimmune Link

Cited by 3 publications

References 35 publications

Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

Vasoactive intestinal peptide inhibits TNF-α-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands

New insights into the role of VIP on the ratio of T‐cell subsets during the development of autoimmune diabetes

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