Adipose Tissue-Derived Mesenchymal Stem Cells Increase Skin Allograft Survival and Inhibit Th-17 Immune Response

Adipose tissue-derived mesenchymal stem cells (ADSC) exhibit immunosuppressive capabilities both in vitro and in vivo. Their use for therapy in the transplant field is attractive as they could render the use of immunosuppressive drugs unnecessary. The aim of this study was to investigate the effect of ADSC therapy on prolonging skin allograft survival. Animals that were treated with a single injection of donor allogeneic ADSC one day after transplantation showed an increase in donor skin graft survival by approximately one week. This improvement was associated with preserved histological morphology, an expansion of CD4+ regulatory T cells (Treg) in draining lymph nodes, as well as heightened IL-10 expression and down-regulated IL-17 expression. In vitro, ADSC inhibit naïve CD4+ T cell proliferation and constrain Th-1 and Th-17 polarization. In summary, infusion of ADSC one day post-transplantation dramatically increases skin allograft survival by inhibiting the Th-17 pathogenic immune response and enhancing the protective Treg immune response. Finally, these data suggest that ADSC therapy will open new opportunities for promoting drug-free allograft survival in clinical transplantation

HuR Controls Glutaminase RNA Metabolism

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment

TLR2, TLR4 and the MYD88 Signaling Pathway Are Crucial for Neutrophil Migration in Acute Kidney Injury Induced by Sepsis

The aim of this study was to investigate the role of TLR2, TLR4 and MyD88 in sepsis-induced AKI. C57BL/6 TLR2(-/-), TLR4(-/-) and MyD88(-/-) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Twenty four hours later, kidney tissue and blood samples were collected for analysis. the TLR2(-/-), TLR4(-/-) and MyD88(-/-) mice that were subjected to CLP had preserved renal morphology, and fewer areas of hypoxia and apoptosis compared with the wild-type C57BL/6 mice (WT). MyD88(-/-) mice were completely protected compared with the WT mice. We also observed reduced expression of proinflammatory cytokines in the kidneys of the knockout mice compared with those of the WT mice and subsequent inhibition of increased vascular permeability in the kidneys of the knockout mice. the WT mice had increased GR1(+low) cells migration compared with the knockout mice and decreased in GR1(+high) cells migration into the peritoneal cavity. the TLR2(-/-), TLR4(-/-), and MyD88(-/-) mice had lower neutrophil infiltration in the kidneys. Depletion of neutrophils in the WT mice led to protection of renal function and less inflammation in the kidneys of these mice. Innate immunity participates in polymicrobial sepsis-induced AKI, mainly through the MyD88 pathway, by leading to an increased migration of neutrophils to the kidney, increased production of proinflammatory cytokines, vascular permeability, hypoxia and apoptosis of tubular cells.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Institute of Science and Technology (INCT)Universidade Federal de São Paulo, Dept Med, Disciplina Nefrol, São Paulo, BrazilUniv São Paulo, Dept Imunol, Lab Imunobiol Transplantes, São Paulo, BrazilHosp Israelita Albert Einstein, IIEP, São Paulo, BrazilUniv Fed Triangulo Mineiro, Uberaba, BrazilUniversidade Federal de São Paulo, Dept Med, Disciplina Nefrol, São Paulo, BrazilFAPESP: 07/07139-3Web of Scienc

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

Catálogo Taxonômico da Fauna do Brasil: setting the baseline knowledge on the animal diversity in Brazil

The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others

Leptin: a central modulator of imune responses.

A leptina é um mediador tanto de respostas neuroendócrinas como imunes, e tem sido associada a diversas autoimunidades. O nosso objetivo foi estudar a importância da leptina na modulação da resposta imunológica no transplante experimental, com ênfase em seu papel na plasticidade de linfócitos T e de células dendríticas (DC). Observamos que os animais deficientes em leptina têm uma sobrevida aumentada do enxerto de pele e uma menor frequência de células Th1 e maior T reguladoras (Treg), Th2 e Th17. Ademais, células T CD4+ naive diferenciam-se mais eficientemente em células Treg e Th17 tanto com DC como sem DC, na ausência de leptina. Nossos dados indicam que BMDC, imaturas e maduras, é comprometida na ausência de leptina, induzindo menor proliferação de linfócitos CD4+ e maior geração/expansão de células Treg, Th17 e Th2. Assim, a ausência de leptina resultou num predomínio de células Treg um padrão Th2 que, em conjunto com o perfil tolerogênico das DC, poderiam ser um dos mecanismos responsáveis pelo aumento da sobrevida do enxerto alogenêico de pele.Leptin is a mediator of both neuroendocrine and immune responses, and has been associated with several autoimmune diseases. Our objective was to study the importance of leptin in modulating the immune response in experimental transplantation, with emphasis on its role in the plasticity of T lymphocytes and dendritic cells (DC). We observed that animals leptin deficient had an increased skin graft survival and lower frequency of Th1 and increased regulatory (Treg), Th2 and Th17 T cells. Furthermore, naive CD4+ T cells differentiate more efficiently in Treg and Th17 cells, with DC and without DC, in the absence of leptin. Our data indicate that BMDC, mature and immature, is compromised in the absence of leptin, leading to less proliferation of CD4+ and increased generation / expansion of Treg cells, Th2 and Th17. Thus, the lack of leptin resulted in a predominance of Th2 and Treg T cells, which together with the profile of tolerogenic DC could be one of the mechanisms responsible for increased survival of allograft skin

Study of the immunologic molecular profile in operational tolerance kidney transplanted individuals

A indução de tolerância ao aloenxerto, no contexto do transplante clínico, é um dos maiores desafios da imunologia. Existem pacientes transplantados que mesmo após a retirada de imunossupressores mantêm a função estável do aloenxerto. Este estado é chamado de tolerância operacional. Nosso objetivo foi analisar se os indivíduos em tolerância operacional tem um perfil imunológico molecular diferencial em relação aos outros grupos clínicos, visando identificar potenciais mecanismos envolvidos na manutenção desse estado de não agressão ao órgão transplantado. Analisamos 10 doadores renais saudáveis (Sau) e 32 indivíduos transplantados renais, sendo 4 tolerantes operacionais (TO), 11 com rejeição crônica (RC), 12 com função renal estável e imunossupressão convencional (Est) e 5 com função renal estável e baixa imunossupressão (BI). Analisamos a expressão gênica, em células mononucleares do sangue, de um painel de moléculas predominantemente imunorreguladoras ou próinflamatórias (REGULA/INFLAMA), por PCR em tempo real, em duas amostras, com intervalos de 4-6 meses. Quantificamos as células T CD4+CD25+Foxp3+, por citometria de fluxo, e estudamos a ativação de duas vias de sinalização, IL-6/STAT3 e IL-4/STAT6, por PhosFlow, nos diferentes grupos de estudo. Nós observamos algumas diferenças significativas entre os indivíduos TO e os outros grupos de estudo, (p<0,05). A expressão dos genes de TGF- e TGF-R foi maior no grupo de indivíduos TO em comparação aos grupos Est e BI, analisando-se 2 tempos distintos. A expressão de GATA-3 foi maior no grupo TO comparado a todos os outros grupos de estudo. A expressão gênica de Foxp3 foi maior no grupo TO comparado aos grupos RC e BI, apenas quando analisamos as 2 amostras. Neste painel REGULA/INFLAMA, o grupo TO teve um predomínio de modificações do tipo REGULA, em ambos os tempos estudados, e maior estabilidade na expressão gênica entre as 2 amostras. Em relação as células T CD4+CD25+Foxp3+, os grupos RC e Est tiveram menores números absolutos e porcentagens em comparação aos outros grupos. O grupo TO teve uma quantidade dessas células semelhantes aos grupos Sau e BI. No estudo das vias de sinalização observamos que a fosforilação de STAT6, na região de monócitos, foi menor em indivíduos TO quando comparada a todos os outros grupos estudados. O painel de moléculas REGULA/INFLAMA, utilizado neste estudo, permitiu determinar um perfil imunológico molecular com características predominantemente imunorreguladoras no grupo TO. O perfil de fosforilação da via de sinalização IL-4/STAT6 nos indivíduos TO, na região de monócitos, nos permite interpretar que essas vias sejam mobilizadas de forma diferente, podendo participar deste estado de não agressão ao enxerto. A redução de células T CD4+CD25+Foxp3+ nos indivíduos com imunossupressão convencional (grupos RC e Est) nos permite interpretar que a imunossupressão afeta essa população celular, potencialmente imunorreguladora. O maior número de células T CD4+CD25+Foxp3+, nos indivíduos TO e BI nos permite sugerir que essas células tenham um papel importante no estado de tolerância operacional. Também o fator de transcrição GATA-3 parece desempenhar um importante papel na indução/manutenção do estado de TO, sugerindo que um desvio Th2 seja relevante para a manutenção deste estado. Os nossos resultados nos permitem interpretar que o estado de tolerância operacional tem uma repercussão sistêmica e que essas moléculas parecem ser relevantes e talvez dominantes neste estado de homeostase no contexto do transplante renal humano.standard immunosuppression, lead us to suggest that these cells may be affected by immunosuppression. Moreover, the higher numbers of CD4+CD25+Foxp3+ T cells observed in TO and BI individuals suggest that these cells may have an important role in the induction/maintenance of these two homeostatic states of minimal, or of no aggression to the graft. Furthermore, the higher mRNA expression of GATA-3, in the TO group, suggests that a Th2 deviation may also be relevant to the maintenance of operational tolerance. Our results allowed us to interpret that the state of operational tolerance has systemic repercussion, and that the molecules studied in our work may be relevant to the process of homeostasis in the context of human kidney transplantation

Dendritic cells: immune response in infectious diseases and autoimmunity

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