Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to assess the possible use of viola in therapeutic approaches in human autoimmune diseases.
Tolerogenic dendritic cells (DCs) are widely studied for their possible use in the treatment of inflammatory disorders, such as autoimmune diseases. One of the obstacles for the use of this cell-based therapy is the characterization of drugs that are able to modulate DCs. We have previously shown that chloroquine (CQ), an antimalarial agent, has the ability to modulate DCs towards a tolerogenic phenotype. 1 These tolerogenic DCs are able to suppress the development of experimental autoimmune encephalomyelitis (EAE), a T cell-driven mouse model of human multiple sclerosis. In addition, several studies have proposed that nitric oxide (NO) plays a major role in the differentiation of regulatory T cells (Tregs) and the suppression of Th1/Th17 cells. 2,3 However, little is known about the role of DC-derived NO in the modulation of inflammatory autoimmune responses. Thus, we aimed to evaluate whether NO plays a role in the tolerogenic activity of CQ-treated DCs (CQDCs). We found that CQ induces DC production of NO and expression of indoleamine 2,3-dioxygenase (IDO), as well as inducible nitric oxide synthase (iNOS). In addition, CQ-DCs stimulated the differentiation of Tregs at the expense of Th1/ Th17 cells. On the other hand, iNOS 2/2 DCs did not acquire a tolerogenic phenotype following CQ treatment. Rather, CQDCs iNOS2/2 stimulated the differentiation of Th1/Th17 cells as well as Tregs. In a therapeutic approach, CQ-DCs iNOS2/2 were unable to suppress the development of EAE. Gene expression analyses of central nervous system (CNS) tissue from mice that received CQ-DCs iNOS2/2 showed an increased expression of inflammatory modulators compared with mice that received CQ-DCs WT . In this work, we show that NO is an important factor in the modulatory activity of tolerogenic dendritic cells.DCs are antigen-presenting cells that can dictate the course of the immune response via the modulation and activation of naive T cells. DC modulation is a possible approach to address the immunosuppression that is often caused by tumors 4 and the exacerbated immune response observed in autoimmune diseases. 5 Multiple sclerosis, one such autoimmune disease, is a debilitating condition that affects the CNS. Studies in EAE, an experimental mouse model of multiple sclerosis, have found that much of the immunological etiology of the disease development is due to the activity of Th1/Th17 cells, and these studies have found that NO plays a major role in disease progression. 2 To verify whether NO is involved in the modulatory activity of tolerogenic DCs, we generated DCs from bone marrow precursors obtained from wild-type (DCs WT ) and iNOS 2/2 (DCs iNOS2/2 ) mice and treated these DCs with CQ or vehicle (PBS-DCs WT ). All protocols involving laboratory animals were approved by the institutional committee (protocol no. 2687-1). NO measurements revealed that CQ treatment induced DCs WT to produce large amounts of NO in an iNOS-dependent manner (Figure 1a). It has been demonstrated that CQ administration results in NO production by the endot...
Paracoccidioidomycosis is a systemic infection prevalent in Latin American countries. Disease develops after inhalation of Paracoccidioides brasiliensis conidia followed by an improper immune activation by the host leucocytes. Dendritic cells (DCs) are antigen-presenting cells with the unique ability to direct the adaptive immune response by the time of activation of naive T cells. This study was conducted to test whether extracts of P. brasiliensis would induce maturation of DCs. We found that DCs treated with extracts acquired an inflammatory phenotype and upon adoptive transfer conferred protection to infection. Interestingly, interleukin-10 production by CD8(+) T cells was ablated following DC transfer. Further analyses showed that lymphocytes from infected mice were high producers of interleukin-10, with CD8(+) T cells being the main source. Blockage of cross-presentation to CD8(+) T cells by modulated DCs abolished the protective effect of adoptive transfer. Collectively, our data show that adoptive transfer of P. brasiliensis-modulated DCs is an interesting approach for the control of infection in paracoccidioidomycosis.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-dependent disease that mimics human multiple sclerosis (MS). The inflammation in the central nervous system (CNS) is a hallmark in these autoimmune inflammatory conditions [1]. Therefore, the development of new drugs that target the infiltration of inflammatory cells to the CNS is desired [2,3]. In this context, accumulating evidences place antimalarial drugs as immunomodulatory agents. For instance, administration of chloroquine, a weak base that has tropism toward acidic organelles, was shown to modulate a series of inflammatory diseases, including EAE [4,5]. On the other hand, primaquine (PQ), a drug analogous to chloroquine [6], has much less toxicity and is poorly investigated in the control of inflammation.In this study, we aimed to evaluate whether PQ administration is able to reduce EAE severity. For that purpose, we induced EAE in C57BL/6 mice through subcutaneous injection of 100 lg of MOG 35-55 peptide alongside with 200 ng of pertussis toxin, as previously described [7]. When the clinical signs of EAE started to appear, mice were treated with PQ (3 mg/kg, intraperitoneally) for five consecutive days and disease outcome was evaluated (EAE+PQ group). Mice treated with vehicle (PBS) were used as controls (EAE group). We observed that PQ treatment significantly reduced the development of EAE ( Figure 1A). Interestingly, disease amelioration correlated with lower infiltration of cells in the CNS ( Figure 1B). Notwithstanding, the frequency of Iba-1 + cells (microglia, macrophages, and dendritic cells) was found reduced in the EAE+PQ group compared with untreated EAE-bearing mice, suggesting that probably the demyelination process is reduced in the CNS of EAE+PQ mice ( Figure 1B). To evaluate whether glial cells are affected by PQ treatment, slices were stained for glial fibrillary acidic protein (GFAP) production. Our results showed that EAE+PQ mice presented lower expression of GFAP in comparison with the EAE group ( Figure 1B). Of note, PQ treatment by itself did not induce GFAP expression.Collectively, these results show that improvement in EAE+PQ mice correlated with a reduction in cellular infiltration and gliosis. To investigate whether mediators of inflammation are involved in disease amelioration, the gene expression levels of inflammationrelated cytokines and transcription factors were analyzed. Results showed that levels of FOXP3, IL-10, and TGF-b were significantly increased, while the levels of TNF-a, IL-17, IFN-c, and GATA-3 were decreased in the CNS of EAE+PQ mice compared with the control ( Figure 1C). Unexpectedly, levels of Th17 cell-related transcription factor, RORct, were found reduced in EAE-bearing mice compared with na€ ıve mice, showing that modulation of this transcription factor is not a key element in PQ-induced EAE amelioration.The increased expression in FOXP3, IL-10, and TGF-b in the CNS of EAE+PQ mice suggests that the treatment induces the expansion of regulatory T (Treg) cells. To confirm this hypothesis, na€ ıve m...
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