Streptozotocin causes T1D by inducing the translocation of intestinal bacteria into pancreatic lymph nodes and driving the development of pathogenic Th1 and Th17 cells through NOD2 receptor.

Although a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3−/− mice, but not in ASC−/− mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome b and cytochrome c, but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3−/− macrophages. Finally, mDNA administration in vivo increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3−/− mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1-dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D.

NZB mice spontaneously develop autoimmune hemolytic anemia (AIHA). The red blood cell (RBC) autoantigen bound by pathogenic IgG autoantibodies, previously designated "X", was identified by immunoprecipitation. Autoantibody eluted from the RBC of AIHA-positive NZB mice precipitated a 105-kDa antigen that was identical in apparent molecular mass to Band 3, the RBC anion channel protein. Furthermore, the immunoblotted antigen also reacted specifically with BRIC 132, a monoclonal antibody against Band 3. The results, therefore, demonstrate that Band 3 bears autoantigenic epitopes that are important in the pathogenesis of AIHA in the NZB mouse.

Systemic arterial hypertension has been associated with the majority deaths from cardiovascular disease, especially among the elderly population, and the imbalance between antioxidant and pro-oxidants has been associated with hypertension. This study analyzed the acute responses of cardiorespiratory and oxidative stress parameters to low intensity aerobic exercise (LIAE) with blood flow restriction (BFR) in hypertensive elderly women. The experimental group consisted of 16 hypertensive women (67.2 ± 3.7 years) who underwent a progressive treadmill test and performed three exercise protocols in random order: high intensity (HIAE), low intensity aerobic exercise (LIAE) and low intensity aerobic exercise with blood flow restriction (LIAE + BFR). Data analysis showed that blood pressure and heart rate augmented from rest to post effort (p < 0.05) and reduced from post effort to recovery (p < 0.05) in all protocols. The values of lipid peroxidation were higher after 30 min of recovery when compared to the moment at rest in the LILIAE + BFR (p < 0.05). The same occurred with glutathione-S-transferase and superoxide dismutase activity. However, non-protein thiols levels (NPSH) reduced after 30 min of recovery when compared to the moment at rest in the LILIAE + BFR protocol (p < 0.05). In the HIAE and LIAE + BFR protocols, the levels of NPSH were lower at 30 min of recovery when compared to the same moment in the LIAE protocol (p < 0.05). LIAE + RBF produces an oxidative status and hemodynamic stimulus similar to HIAE. Taken together, these results support the indication of LIAE with BFR in chronic intervention protocols, with potential benefits for the hypertensive elderly population.

The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi-induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi. Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi-induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi-induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi-infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the bona fide culprit of Chagas disease cardiomyopathy.