Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) ... more Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) are of special interest for organ transplantation and for the treatment of autoimmune diseases. In the present work, we have developed two humanized anti-CD3 antibodies. These molecules were shown to bind to human CD3, though less efficiently, and display less mitogenic activity than OKT3. These results prompted us to investigate whether this reduced mitogenic potential was associated with the development of anti-inflammatory properties. Indeed, in peripheral blood mononuclear cells (PBMCs), the humanized antibody versions induced a predominantly anti-inflammatory cytokine profile, in contrast with the pro-inflammatory profile induced by OKT3. Neither OKT3 nor the humanized versions induced the expression of IL-4, IL-2 or TGF-beta. Both humanized antibodies induced significantly lower production of IFN-gamma and IL-5 and slightly higher production of IL-10 than OKT3. This immunomodulatory profile was most evident by the 80-fold higher ratio of IL-10/IFN-gamma production in PBMCs cultured in the presence of the humanized antibodies, compared to those stimulated with OKT3. Furthermore, these humanized anti-CD3 antibodies induced a late FOXP3 gene expression while OKT3 led to a more transient expression of FOXP3. Taken our results, we suggest that these humanized anti-CD3 antibodies may promote the development of T cells with immunoregulatory activity.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global o... more The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects the lungs and may cause several immune-related complications such as lymphocytopenia and cytokine storm which are associated with the severity of the disease and predict mortality1,2. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is not fully understood. Here we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells in a mechanism that also requires ACE2 and TMPRSS2. Once inside T helper cells, SARS-CoV-2 assembles viral factories, impairs cell function and may cause cell death. SA...
Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type ... more Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1β (IL1β) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1β is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4-overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1β. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1β levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NL...
Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1... more Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world’s population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients and do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls. Our results revealed differentially regulated proteins in pathways related to mitochondrial function, oxidative phosphorylation, cell cycle control, DNA repair, and neuritogenesis. Moreover, metabolic analysis of NSCs revealed alterations in mitochondrial function in schizophrenia-derived cells. Hence, this study shows that changes in i...
PAHSAs are anti-diabetic and anti-inflammatory lipids. Syed et al. identify numerous experimental... more PAHSAs are anti-diabetic and anti-inflammatory lipids. Syed et al. identify numerous experimental differences that likely account for the failure of Pflimlin et al. to observe PAHSA beneficial effects. The differences include different HFDs resulting in minimal/no glucose intolerance, different assay conditions, an LC-MS protocol that was not validated, and use of olive oil, a bioactive nutrient that improves glucose tolerance, as a vehicle.
Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inf... more Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contras...
Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in huma... more Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause in...
We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid es... more We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis which is a chronic, inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well-tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pre-treated orally with vehicle or 5-PAHSA (10mg/kg) and 9-PAHSA (5mg/kg) once daily for 3 days followed by 10 days of either 0% or 2%-dextran sulfate sodium water, with continued vehicle or PAHSA treatment. Colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone-marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4+ T-cells from syngeneic mice were co-cultu...
Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause o... more Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause of type-2-diabetes. RBP4 is an adipocyte- and liver-derived protein with an important role in insulin-resistance, metabolic syndrome and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity which elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin-resistant and glucose-intolerant and have increased AT macrophages and T-helper1 (Th1) cells. We show that HFD-fed RBP4(-/-) mice have reduced AT inflammation and improved insulin-sensitivity versus wildtype. We also elucidate the mechanism for RBP4-induced macrophage antigen-presentation and subsequent T-cell activation. In RBP4-Ox, AT macrophages display enhanced JNK, Erk and p38 phosphorylation. Inhibition of these pathways and of NFκB reduces activation of macrophages and CD4 T-cells. MyD88 is an adaptor-protein involved in pro-inflammatory signaling. In macrophages from MyD88(-...
Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormona... more Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an ...
Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding-protein 4 (RB... more Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding-protein 4 (RBP4) levels. Elevated RBP4 causes insulin resistance and lowering RBP4 improves glucose homeostasis. Since lowering TTR increases renal clearance of RBP4, we determined if decreasing TTR with antisense oligonucleotides (ASOs) improves glucose metabolism and insulin sensitivity in obesity. TTR-ASO treatment of mice with genetic or dietary-induced obesity resulted in 80-95% decrease in circulating TTR and RBP4. TTR-ASO, but not Control ASO, decreased insulin levels by 30-60% and improved insulin sensitivity in ob/ob mice and high-fat-diet-fed mice as early as 2 weeks of treatment. The reduced insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue inflammation. Body weight was not changed. TTR-ASO treatment decreased LDL cholesterol in high-fat-diet-fed mice. The glucose infusion rate during a hyperinsulinemic-euglycemic clamp was 50% inc...
Journal of the American Society of Nephrology : JASN, Jan 14, 2015
Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbio... more Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the ...
Journal of immunology (Baltimore, Md. : 1950), Jan 27, 2015
Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs c... more Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-1...
Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) ... more Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) are of special interest for organ transplantation and for the treatment of autoimmune diseases. In the present work, we have developed two humanized anti-CD3 antibodies. These molecules were shown to bind to human CD3, though less efficiently, and display less mitogenic activity than OKT3. These results prompted us to investigate whether this reduced mitogenic potential was associated with the development of anti-inflammatory properties. Indeed, in peripheral blood mononuclear cells (PBMCs), the humanized antibody versions induced a predominantly anti-inflammatory cytokine profile, in contrast with the pro-inflammatory profile induced by OKT3. Neither OKT3 nor the humanized versions induced the expression of IL-4, IL-2 or TGF-beta. Both humanized antibodies induced significantly lower production of IFN-gamma and IL-5 and slightly higher production of IL-10 than OKT3. This immunomodulatory profile was most evident by the 80-fold higher ratio of IL-10/IFN-gamma production in PBMCs cultured in the presence of the humanized antibodies, compared to those stimulated with OKT3. Furthermore, these humanized anti-CD3 antibodies induced a late FOXP3 gene expression while OKT3 led to a more transient expression of FOXP3. Taken our results, we suggest that these humanized anti-CD3 antibodies may promote the development of T cells with immunoregulatory activity.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global o... more The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects the lungs and may cause several immune-related complications such as lymphocytopenia and cytokine storm which are associated with the severity of the disease and predict mortality1,2. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is not fully understood. Here we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells in a mechanism that also requires ACE2 and TMPRSS2. Once inside T helper cells, SARS-CoV-2 assembles viral factories, impairs cell function and may cause cell death. SA...
Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type ... more Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1β (IL1β) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1β is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4-overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1β. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1β levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NL...
Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1... more Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world’s population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients and do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls. Our results revealed differentially regulated proteins in pathways related to mitochondrial function, oxidative phosphorylation, cell cycle control, DNA repair, and neuritogenesis. Moreover, metabolic analysis of NSCs revealed alterations in mitochondrial function in schizophrenia-derived cells. Hence, this study shows that changes in i...
PAHSAs are anti-diabetic and anti-inflammatory lipids. Syed et al. identify numerous experimental... more PAHSAs are anti-diabetic and anti-inflammatory lipids. Syed et al. identify numerous experimental differences that likely account for the failure of Pflimlin et al. to observe PAHSA beneficial effects. The differences include different HFDs resulting in minimal/no glucose intolerance, different assay conditions, an LC-MS protocol that was not validated, and use of olive oil, a bioactive nutrient that improves glucose tolerance, as a vehicle.
Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inf... more Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contras...
Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in huma... more Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause in...
We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid es... more We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis which is a chronic, inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well-tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pre-treated orally with vehicle or 5-PAHSA (10mg/kg) and 9-PAHSA (5mg/kg) once daily for 3 days followed by 10 days of either 0% or 2%-dextran sulfate sodium water, with continued vehicle or PAHSA treatment. Colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone-marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4+ T-cells from syngeneic mice were co-cultu...
Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause o... more Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause of type-2-diabetes. RBP4 is an adipocyte- and liver-derived protein with an important role in insulin-resistance, metabolic syndrome and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity which elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin-resistant and glucose-intolerant and have increased AT macrophages and T-helper1 (Th1) cells. We show that HFD-fed RBP4(-/-) mice have reduced AT inflammation and improved insulin-sensitivity versus wildtype. We also elucidate the mechanism for RBP4-induced macrophage antigen-presentation and subsequent T-cell activation. In RBP4-Ox, AT macrophages display enhanced JNK, Erk and p38 phosphorylation. Inhibition of these pathways and of NFκB reduces activation of macrophages and CD4 T-cells. MyD88 is an adaptor-protein involved in pro-inflammatory signaling. In macrophages from MyD88(-...
Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormona... more Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an ...
Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding-protein 4 (RB... more Circulating transthyretin (TTR) is a critical determinant of plasma retinol-binding-protein 4 (RBP4) levels. Elevated RBP4 causes insulin resistance and lowering RBP4 improves glucose homeostasis. Since lowering TTR increases renal clearance of RBP4, we determined if decreasing TTR with antisense oligonucleotides (ASOs) improves glucose metabolism and insulin sensitivity in obesity. TTR-ASO treatment of mice with genetic or dietary-induced obesity resulted in 80-95% decrease in circulating TTR and RBP4. TTR-ASO, but not Control ASO, decreased insulin levels by 30-60% and improved insulin sensitivity in ob/ob mice and high-fat-diet-fed mice as early as 2 weeks of treatment. The reduced insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue inflammation. Body weight was not changed. TTR-ASO treatment decreased LDL cholesterol in high-fat-diet-fed mice. The glucose infusion rate during a hyperinsulinemic-euglycemic clamp was 50% inc...
Journal of the American Society of Nephrology : JASN, Jan 14, 2015
Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbio... more Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the ...
Journal of immunology (Baltimore, Md. : 1950), Jan 27, 2015
Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs c... more Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-1...
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