Dectin-1 Activation Exacerbates Obesity and Insulin Resistance in the Absence of MyD88

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant numbers 11/15682-4, 12/02270-2, 15/18121-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Regenera INCT Process Grant 465656/2014-5). JL is funded by the NIH/NIDDK R01DK106210. GDB is funded by the Wellcome Trust and the MRC Centre for Medical Mycology. Open access journalPeer reviewedPublisher PD

Balance between the two kinin receptors in the progression of experimental focal and segmental glomerulosclerosis in mice

Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end-stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation, whereas the role of its receptor 2 (B2RBK; also known as BDKRB2) in FSGS has not been studied. FSGS was induced in wild-type and B2RBK-knockout mice by a single intravenous injection of Adriamycin (ADM). in order to further modulate the kinin receptors, the animals were also treated with the B2RBK antagonist HOE-140 and the B1RBK antagonist DALBK. Here, we show that the blockage of B2RBK with HOE-140 protects mice from the development of FSGS, including podocyte foot process effacement and the re-establishment of slit-diaphragm-related proteins. However, B2RBK-knockout mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was upregulated after the injection of ADM and this upregulation was exacerbated in B2RBK-knockout animals. Furthermore, treatment with HOE-140 downregulated the B1RBK receptor. the blockage of B1RBK in B2RBK-knockout animals promoted FSGS regression, with a less-inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in an FSGS model and suggest a possible cross-talk between them in the progression of disease.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Clin & Expt Immunol Lab, Div Nephrol, BR-04023900 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci 4, Dept Immunol, Lab Transplantat Immunobiol, BR-05508000 São Paulo, BrazilUniversidade Federal de São Paulo, Translat Med Div, Clin & Expt Immunol Lab, BR-04039002 São Paulo, BrazilInst Butantan, Lab Cellular Biol, BR-05503900 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Biophys, BR-04023062 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilINSERM, Unite Mixte Rech 699, F-75870 Paris, FranceAlbert Einstein Hosp, Inst Israelita Ensino & Pesquisa Albert Einst, Renal Transplantat Unit, BR-05521000 São Paulo, BrazilUniversidade Federal de São Paulo, Clin & Expt Immunol Lab, Div Nephrol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Translat Med Div, Clin & Expt Immunol Lab, BR-04039002 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Biophys, BR-04023062 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04023062 São Paulo, BrazilFAPESP: 2012/05605-5FAPESP: 07/07139-3FAPESP: 12/02270-2CNPq: 140739/2008-4Web of Scienc

Role of NKT cells in adenine-induced tubulointerstitial nephritis

As doencas que afetam o compartimento tubulo-intersticial renal sao numerosas e variadas. A patogenese das doencas renais envolve a participacao de varios elementos da resposta imune. As celulas NKT constituem uma populacao distinta de linfocitos caracterizada pela reatividade a glicolipidios apresentados pela molecula CD1d. O objetivo do nosso trabalho foi analisar a participacao das celulas NKT em modelo experimental de nefrite tubulo-intersticial induzida pela inGestão excessiva de adenina. Utilizamos camundongos selvagens C57Bl/6j e camundongos nocautes para os genes Jα18 e CD1d, de 8-10 semanas. A racao contendo 0,25% de adenina foi oferecida aos animais durante 10 dias e os animais controle receberam a dieta padrao. Outro grupo de animais selvagens foram injetados uma vez com os agonistas de celulas NKT, αGalCer ou Sulfatideo, no mesmo dia de inicio da racao com adenina. Os animais foram sacrificados no 10º dia apos inicio da racao de adenina e amostras de sangue e tecido renal foram coletadas para analise da funcao renal, expressao genica, histologia e imunohistoquimica. Os dados foram apresentados atraves de media±desvio padrao e o teste ANOVA foi utilizado para comparacao dos grupos. Em relacao aos grupos de animais nocautes alimentados com racao suplementada com adenina, observamos um aumento significativo na expressao genica de KIM-1 e TNF-α no tecido renal, em relacao aos WT do grupo adenina. Houve tambem aumento significativo da fibrose intersticial renal nos animais Jα18 -/- do grupo adenina em relacao aos WT do mesmo grupo. No grupo de animais injetados com agonistas de celulas NKT, observamos diminuicao dos niveis de creatinina serica nos animais que receberam αGalCer e adenina e tambem nos que receberam Sulfatideo e adenina. Da mesma forma, houve diminuicao da expressao genica de IL-6 e TNF-α, reducao significativa da porcentagem de fibrose intersticial e da marcacao para FSP-1 e α-SMA nos animais do grupo adenina injetados com αGalCer e Sulfatideo, em relacao aos WT do grupo adenina. Portanto, juntos, esses dados indicam que as celulas NKT participam atenuando o processo de lesao renal induzida pela adenina. A ausencia dessas celulas leva a uma piora do quadro renal e a ativacao das mesmas e capaz de melhorar a funcao renal dos animais WT quando submetidos a inGestão de adeninaBV UNIFESP: Teses e dissertaçõe

Role of NKT cells in intestinal homeostasis and inflammation.

As células NKT compreendem um grupo distinto de linfócitos caracterizados pela reatividade a glicolipídios apresentados pela molécula CD1d. Em nosso trabalho, nós investigamos a participação das células NKT na homeostase intestinal utilizando animais nocautes para essas células e também caracterizamos os subtipos de NKT no intestino. Nos animais nocautes observamos que a ausência de células NKT influencia a microbiota e a homeostase intestinal. Os animais nocautes possuem diminuição no filo Firmicutes, diminuição dos níveis de IgA nas fezes e de TGF-β no intestino. Esses animais também são mais suscetíveis à colite induzida por DSS, apresentando menor sobrevida, menor tamanho do cólon e aumento no score. Nos animais selvagens, a indução do subtipo NKT10 diminuiu a inflamação intestinal, não causou intensa redução do cólon e reduziu a frequência de células NKT e do subtipo NKT17 no intestino. Nossos resultados indicam que as células NKT intestinais são peças importantes para a homeostase intestinal e para a composição da microbiota intestinal.NKT cells comprise a distinct group of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. In our work, we investigated the involvement of NKT cells in intestinal homeostasis using knockout (KO) mice and we also characterized NKT subtypes in the intestine. The absence of NKT cells in KO mice influenced the intestinal microbiota and homeostasis. KO mice had a decrease in the Firmicutes phyla, in the levels of fecal IgA and TGF-β in the intestine. These mice are also more susceptible to DSS-induced colitis, exhibiting worse survival, severe shortening of the colon and higher score. In wild type mice, the induction of the NKT10 subtype decreased intestinal inflammation, did not cause intense reduction of colon and reduced the frequency of NKT cells and the NKT17 subtype in the intestine. Our results indicate that intestinal NKT cells are important for intestinal homeostasis and microbiota composition

Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis

Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (J alpha 18(-/-)) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists alpha-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in J alpha 18(-/-) mice and in wild-type alpha-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-beta and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.Univ Sao Paulo, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo, BrazilUniv Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Lab Hypertens, Sao Paulo, BrazilUniv Fed Sao Paulo, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, BrazilUniv Sao Paulo, Inst Biomed Sci 4, Ave Prof Lineu Prestes 1730, BR-05508000 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, BrazilWeb of Scienc

Mesenchymal stromal cells modulate gut inflammation in experimental colitis

Inflammatory bowel diseases (IBDs) affect millions of people worldwide and their frequencies in developed countries have increased since the twentieth century. In this context, there is an intensive search for therapies that modulate inflammation and provide tissue regeneration in IBDs. Recently, the immunomodulatory activity of adipose tissue-derived mesenchymal stromal cells (ADMSCs) has been demonstrated to play an important role on several immune cells in different conditions of inflammatory and autoimmune diseases. In this study, we explored the immunomodulatory potential of ADMSC in a classical model of DSS-induced colitis. First, we found that treatment of mice with ADMSC ameliorated the severity of DSS-induced colitis, reducing colitis pathological score and preventing colon shortening. Moreover, a prominent reduction of pro-inflammatory cytokines levels (i.e., IFN-gamma, TNF-alpha, IL-6 and MCP-1) was observed in the colon of animals treated with ADMSC. We also observed a significant reduction in the frequencies of macrophages (F4/80(+)CD11b(+)) and dendritic cells (CD11c(+)CD103(+)) in the intestinal lamina propria of ADMSC-treated mice. Finally, we detected the up-regulation of immunoregulatory-associated molecules in intestine of mice treated with ADMSCs (i.e., elevated arginase-1 and IL-10). Thus, this present study demonstrated that ADMSC modulates the overall gut inflammation (cell activation and recruitment) in experimental colitis, providing support to the further development of new strategies in the treatment of intestinal diseases.FAPESPCAPESCNPqUniv Sao Paulo, Inst Biomed Sci 4, Dept Immunol, Sao Paulo, BrazilUniv Fed Sao Paulo, Nephrol Div, Dept Med, Sao Paulo, BrazilUniv Fed Alagoas, Inst Biol Sci & Hlth, Alagoas, BrazilUniv Sao Paulo, Sch Med, LIM 16, Sao Paulo, BrazilAv Prof Lineu Prestes 1730 Lab 238 Cidade Univ, BR-05508000 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Nephrol Div, Dept Med, Sao Paulo, BrazilFAPESP: 2012/02270-2, 2012/16794-3, 2013/25327-2Web of Scienc