Impaired toll-like receptor signalling in peripheral B cells from newly diagnosed type-2 diabetic subjects

Madhumitha, Haridoss; Mohan, Viswanathan; Kumar, Nathella Pavan; Pradeepa, Rajendra; Babu, Subash; Aravindhan, Vivekanandhan

doi:10.1016/j.cyto.2015.04.010

Cited by 11 publications

(16 citation statements)

References 14 publications

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“…Few studies in humans have directly investigated whether B-cell function is impaired with obesity; therefore, this was first addressed by testing how ex vivo B-cell cytokine secretion and antibody production were influenced in obese subjects. Notably, IL-6 secretion was lowered upon BCR/TLR9 activation, which agrees with a report revealing that B-cell cytokine secretion can be suppressed in early stage diabetics (27). However, the cytokine data were not in complete agreement with results showing LPS enhances some pro-inflammatory cytokines in obesity from human or mouse B-cells upon ex vivo stimulation (28).…”

Section: Discussionsupporting

confidence: 92%

“…In contrast, much less is known about the influence of obesity on B-cell cytokine secretion and antibody production outside of the context of adipose tissue inflammation (26). There are some conflicting reports suggesting that B-cell activity could be impaired with type II diabetes, a co-morbidity associated with obesity (20, 27). In obese type II diabetic mice, B-cells secrete pro-inflammatory cytokines, similar to diabetic and/or obese patients with elevated fasting glucose (20, 28).…”

Section: Introductionmentioning

confidence: 99%

“…In obese type II diabetic mice, B-cells secrete pro-inflammatory cytokines, similar to diabetic and/or obese patients with elevated fasting glucose (20, 28). On the other hand, newly diagnosed diabetics have suppressed B-cell inflammatory cytokines upon stimulation whereas antibody production is reported to be normal upon influenza vaccination (27, 29). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

Kosaraju

Guesdon

Crouch

et al. 2017

The Journal of Immunology

113

126

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Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B-cell function. However, there is limited information about the influence of obesity on B-cell function and underlying factors that modulate B-cell responses. Therefore, we studied B-cell cytokine secretion and/or antibody production across obesity models. In obese humans, B-cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B-cells. Furthermore, the high fat diet lowered bone marrow B-cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B-cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA3). DHA, an essential fatty acid with immunomodulatory properties, was tested since its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished antibody titers whereas the Western diet + DHA improved titers. Mechanistically, DHA did not directly target B-cells to elevate antibody levels. Instead, DHA increased the concentration of the downstream specialized pro-resolving lipid mediators (SPMs) 14-HDHA, 17-HDHA, and protectin DX. All three SPMs were found to be effective in elevating murine antibody levels upon influenza infection. Altogether, the results demonstrate that B-cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

Kosaraju

Guesdon

Crouch

et al. 2017

The Journal of Immunology

113

126

View full text Add to dashboard Cite

show abstract

“…The participants for this study were selected from the outpatients visiting Dr. Mohan’s Diabetes Specialities Centre, Chennai based on the inclusion and exclusion criteria as reported previously [19]. Institutional ethical approval (Ref No-MDRF-EC/SOC/2009//05) was obtained for this study.…”

Section: Methodsmentioning

confidence: 99%

TLR-induced secretion of novel cytokine IL-27 is defective in newly diagnosed type-2 diabetic subjects

et al. 2018

Self Cite

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Toll-like receptors (TLRs), the innate immune receptors, act as sentinels bridging both innate and adaptive arms of immunity. In the present study, we estimated TLR-induced secretion of IL-27, IL-12, IL-23, IL-8, IP-10, IL-17, IL-6 and TNF-α (by ELISA) and expression of Human Leukocyte Antigen- (Human Leukocyte Antigen - antigen D Related (HLA-DR), CD69, CD80 (also known asB7-1) (by flowcytometry) and Activating Transcription Factor 3(ATF3) (by qRT-PCR) in whole blood cultures of control and type-2 diabetic (both newly diagnosed/NDD and known/KDM) subjects. TLR-induced secretion of IL-27 was significantly reduced in the NDD group compared to the control (Normal Glucose Tolerance (NGT)) and KDM groups. On the other hand, the expression of CD80 was significantly upregulated in both the monocytes and B cells in KDM group. This was associated with increased T cell activation (CD3+CD69+HLA-DR+) with increased IL-17 and reduced TNF-α secretion in this group. Impaired TLR-induced IL-27 secretion and augmented expression of antigen presentation molecules result in chronic T cell activation which may fuel T cell-mediated inflammation in type-2 diabetes.

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“…TLR activation triggers a downstream signal cascade, which stimulates the secretion of large amounts of pro-inflammatory factors, thereby initiating an inflammatory response (Madhumitha et al, 2015;Xu et al, 2015). In total, 11 members of the TLR family have been identified so far (TLR-1-11), among which TLR-2 and TLR-4 have the widest distribution, broadest spectrum for pathogen recognition, and release the greatest variety of products.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

Zhao

Liu

2016

Genet. Mol. Res.

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ABSTRACT. Diabetic retinopathy (DR), a major complication of diabetes mellitus, is the leading cause of adult blindness. The Toll-like receptor (TLR) family is believed to be involved in the pathogenesis and progression of DR. Here, we investigated the expression profiles of TLR-2 and TLR-4 in retinal ganglion cells (RGCs), in an attempt to elucidate the role of these molecules in the etiology of DR. In vitro cultured RGCs were divided into control and high-glucose groups. The mRNA and protein levels of TLR-2, TLR-4, and nuclear factor (NF)-κB were detected by real-time PCR and western blotting. RGCs were further transfected with specific siRNA targeting TLR2/TLR4; the proliferation of transfected RGCs and their tumor necrosis factor (TNF)-α and interleukin (IL)-8 secretory capacity were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assays (ELISA), respectively. In a high-glucose environment, TLR-2/4 expression was significantly upregulated in RGCs (while their viability decreased); additionally, NF-κB expression and secretion of TNF-α and IL-8 were significantly increased. Co-silencing of the TLR-2 and TLR-4 genes inhibited NF-κB expression and TNF-α/IL-8 secretion, while increasing the survival rate of RGCs. Therefore, a high-glucose environment can potentiate the expression of TLR-2 and TLR-4 in RGCs, activate the downstream signaling pathway, and increase the secretion of pro-inflammatory factors, thereby aggravating DR.

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Impaired toll-like receptor signalling in peripheral B cells from newly diagnosed type-2 diabetic subjects

Cited by 11 publications

References 14 publications

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

TLR-induced secretion of novel cytokine IL-27 is defective in newly diagnosed type-2 diabetic subjects

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

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