Effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal cord of diabetic rats

2020 ◽  
Vol 16 (4) ◽  
pp. 293-301
Author(s):  
A. Kaki ◽  
M. Nikbakht ◽  
A.H. Habibi ◽  
H.F. Moghadam
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Immune Responses ◽  
Diabetic Neuropathy ◽  
Aerobic Exercise ◽  
Inflammatory Mediators ◽  
Innate Immune ◽  
Moderate Intensity ◽  
Innate Immune Responses ◽  
Tnf Α

Neuronal inflammation is one of the pathophysiological causes of diabetes neuropathic pain. The purpose of this research was to determine the effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal dorsal horn in rats with diabetic neuropathic pain. 40 eight-week-old male Wistar rats (weight range 220±10.2 g) were randomly divided into four groups of (1) sedentary diabetic neuropathy (SDN), (2) training diabetic neuropathy (TDN), (3) training control (TC), and (4) sedentary control (SC). Diabetes was induced by injection of streptozocin (50 mg/kg). Following confirmation of behavioural tests for diabetes neuropathy, the training groups performed 6 weeks of moderate-intensity aerobic exercise on the treadmill. The expression of Toll like receptor (TLR)4, TLR2, tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 genes in L4-L6 spinal cord sensory neurons was measured by Real Time PCR. Two-way ANOVA and Bonferroni’s post hoc tests were used for statistical analysis. After performing aerobic exercise protocol, the TDN compared to the SDN showed a significant decrease in the mean score of pain in the formalin test and a significant increase in the latency in Tail-Flick test was observed. The expression of TLR4, TLR2, TNF-α and IL-1β genes was significantly higher in the SDN than in the SC group (P<0.05). The expression of the above genes in the TDN was significantly lower than the SDN group (P<0.05). Also, the expression level of IL-10 gene was significantly higher in the TDN than the SDN group (P<0.05). Aerobic exercise improved sensitivity of nociceptors to pain-inducing agents in diabetic neuropathy due to inhibition of inflammatory receptors and increased levels of anti-inflammatory agents in the nervous system. Thus, aerobic exercise should be used as a non-pharmacological intervention for diabetic patients to reduce neuropathic pain.

scholarly journals Toll-Like Receptor-Initiated Testicular Innate Immune Responses in Mouse Leydig Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2827-2836 ◽  
Author(s):  
Tao Shang ◽  
Xiaoyan Zhang ◽  
Tao Wang ◽  
Bing Sun ◽  
Tingting Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tyrosine Kinases ◽  
Leydig Cells ◽  
Innate Immune ◽  
Inflammatory Factors ◽  
Innate Immune Responses ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tnf Α ◽  
Microbial Infections ◽  
Local Cell

The testis is an immunoprivileged site, where the local cell-initiated testicular innate immune responses play a crucial role in defense against microbial infections. Mechanisms modulating the testicular cell-built defense system remain to be clarified. In this article, we demonstrate that Leydig cells, a major cell population in the testicular interstitium, initiate innate immunity through the activation of Toll-like receptors (TLRs). Several TLRs are expressed in mouse Leydig cells; among these, TLR3 and TLR4 are expressed at relatively high levels compared with other TLR members. Both TLR3 and TLR4 can be activated by their agonists (polyinosinic:polycytidylic acid and lipopolysaccharide) in Leydig cells and subsequently induce the production of inflammatory factors, such as IL-1β, IL-6, TNF-α, and type 1 interferons (IFN) (IFN-α and IFN-β). Notably, the activation of TLR3 and TLR4 suppresses steroidogenesis by Leydig cells. Further, we provide evidence that Axl and Mer receptor tyrosine kinases are expressed in Leydig cells and regulate TLR-mediated innate immune responses negatively. Data presented here describe a novel function of Leydig cells in eliciting testicular innate immune responses that should contribute to the protection of the testis from microbial infections.

scholarly journals Pneumolysin is responsible for differential gene expression and modifications in the epigenetic landscape of primary monocyte derived macrophages

2020 ◽  
Author(s):  
J. Cole ◽  
A. Angyal ◽  
R. D. Emes ◽  
T.J. Mitchell ◽  
M.J. Dickman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Epigenetic Modification ◽  
Transcriptional Response ◽  
Innate Immune ◽  
Global Changes ◽  
Innate Immune Responses ◽  
Transcriptional Responses ◽  
Tnf Α

AbstractEpigenetic modifications regulate gene expression in the host response to a diverse range of pathogens. The extent and consequences of epigenetic modification during macrophage responses to Streptococcus pneumoniae, and the role of pneumolysin, a key Streptococcus pneumoniae virulence factor, in influencing these responses, are currently unknown. To investigate this, we infected human monocyte derived macrophages (MDMs) with Streptococcus pneumoniae and addressed whether pneumolysin altered the epigenetic landscape and the associated acute macrophage transcriptional response using a combined transcriptomic and proteomic approach. Transcriptomic analysis identified 503 genes that were differentially expressed in a pneumolysin-dependent manner in these samples. Pathway analysis highlighted the involvement of transcriptional responses to core innate responses to pneumococci including modules associated with metabolic pathways activated in response to infection, oxidative stress responses and NFκB, NOD-like receptor and TNF signalling pathways. Quantitative proteomic analysis confirmed pneumolysin-regulated protein expression, early after bacterial challenge, in representative transcriptional modules associated with innate immune responses. In parallel, quantitative mass spectrometry identified global changes in the relative abundance of histone post translational modifications (PTMs) upon pneumococcal challenge. We identified an increase in the relative abundance of H3K4me1, H4K16ac and a decrease in H3K9me2 and H3K79me2 in a PLY-dependent fashion. We confirmed that pneumolysin blunted early transcriptional responses involving TNF-α and IL-6 expression. Vorinostat, a histone deacetylase inhibitor, similarly downregulated TNF production, reprising the pattern observed with pneumolysin. In conclusion, widespread changes in the macrophage transcriptional response are regulated by pneumolysin and are associated with global changes in histone PTMs. Modulating histone PTMs can reverse pneumolysin-associated transcriptional changes influencing innate immune responses, suggesting that epigenetic modification by pneumolysin plays a role in dampening the innate responses to pneumococci.Author summaryPneumolysin is a toxin that contributes to how Streptococcus pneumoniae, the leading cause of pneumonia, causes disease. In this study, the toxin alters gene expression in immune cells called macrophages, one of the first lines of defence against bacteria at sites of infection. Modulation involved multiple immune responses, including generation of chemical signals coordinating responses in immune cells termed cytokines. In addition, changes were observed in histone proteins that are involved in controlling gene expression in the cell. Pneumolysin reduced early production of the cytokine TNF-α and a medicine vorinostat that modifies these ‘epigenetic’ histone modifications had a similar affect, suggesting epigenetic mechanisms contribute to the ability of pneumolysin to reduce immune responses.

scholarly journals Managing Inflammation after Spinal Cord Injury through Manipulation of Macrophage Function

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Yi Ren ◽  
Wise Young
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Immune Responses ◽  
Potential Effect ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Inflammatory Microenvironment ◽  
Persistent Inflammation ◽  
Cord Injury

Spinal cord injury (SCI) triggers inflammation with activation of innate immune responses that contribute to secondary injury including oligodendrocyte apoptosis, demyelination, axonal degeneration, and neuronal death. Macrophage activation, accumulation, and persistent inflammation occur in SCI. Macrophages are heterogeneous cells with extensive functional plasticity and have the capacity to switch phenotypes by factors present in the inflammatory microenvironment of the injured spinal cord. This review will discuss the role of different polarized macrophages and the potential effect of macrophage-based therapies for SCI.

scholarly journals Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hirohisa Miyashita ◽  
Daisuke Oikawa ◽  
Seigo Terawaki ◽  
Daijiro Kabata ◽  
Ayumi Shintani ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hela Cells ◽  
Nuclear Factor Κb ◽  
Suppressive Effect ◽  
Innate Immune ◽  
Bacterial Invasion ◽  
Innate Immune Responses ◽  
Apoptotic Pathway ◽  
Ubiquitin Chain ◽  
Tnf Α

Nuclear dot protein 52 kDa (NDP52, also known as CALCOCO2) functions as a selective autophagy receptor. The linear ubiquitin chain assembly complex (LUBAC) specifically generates the N-terminal Met1-linked linear ubiquitin chain, and regulates innate immune responses, such as nuclear factor-κB (NF-κB), interferon (IFN) antiviral, and apoptotic pathways. Although NDP52 and LUBAC cooperatively regulate bacterial invasion-induced xenophagy, their functional crosstalk remains enigmatic. Here we show that NDP52 suppresses canonical NF-κB signaling through the broad specificity of ubiquitin-binding at the C-terminal UBZ domain. Upon TNF-α-stimulation, NDP52 associates with LUBAC through the HOIP subunit, but does not disturb its ubiquitin ligase activity, and has a modest suppressive effect on NF-κB activation by functioning as a component of TNF-α receptor signaling complex I. NDP52 also regulates the TNF-α-induced apoptotic pathway, but not doxorubicin-induced intrinsic apoptosis. A chemical inhibitor of LUBAC (HOIPIN-8) cancelled the increased activation of the NF-κB and IFN antiviral pathways, and enhanced apoptosis in NDP52-knockout and -knockdown HeLa cells. Upon Salmonella-infection, colocalization of Salmonella, LC3, and linear ubiquitin was detected in parental HeLa cells to induce xenophagy. Treatment with HOIPIN-8 disturbed the colocalization and facilitated Salmonella expansion. In contrast, HOIPIN-8 showed little effect on the colocalization of LC3 and Salmonella in NDP52-knockout cells, suggesting that NDP52 is a weak regulator in LUBAC-mediated xenophagy. These results indicate that the crosstalk between NDP52 and LUBAC regulates innate immune responses, apoptosis, and xenophagy.

scholarly journals Time-resolved single-cell RNAseq profiling identifies a novel Fabp5-expressing subpopulation of inflammatory myeloid cells in chronic spinal cord injury

2020 ◽  
Author(s):  
Regan Hamel ◽  
Luca Peruzzotti-Jametti ◽  
Katherine Ridley ◽  
Veronica Testa ◽  
Bryan Yu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Immune Responses ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Chronic Spinal Cord Injury ◽  
Time Resolved ◽  
Cord Injury ◽  
Infiltrating Cells

AbstractInnate immune responses following spinal cord injury (SCI) participate in early secondary pathogenesis and wound healing events. Here, we used time-resolved scRNAseq to map transcriptional profiles of SC tissue-resident and infiltrating myeloid cells post-SCI.Our work identifies a novel subpopulation of Fabp5+ inflammatory myeloid cells, comprising both resident and infiltrating cells and displaying a delayed cytotoxic profile at the lesion epicentre, which may serve as a target for future therapeutics.

scholarly journals CD1d-Associated Expression of NF-κB and Cardiac Dysfunction in Diabetic and Obese Mice

2013 ◽  
Vol 26 (1) ◽  
pp. 59-73 ◽  
Author(s):  
R. Madonna ◽  
H. Wu ◽  
H. Shelat ◽  
Y-J. Geng
Keyword(s):  
Immune Responses ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Splenic Tissue ◽  
Innate Immune ◽  
Inflammatory Factors ◽  
Innate Immune Responses ◽  
Obesity And Diabetes ◽  
Tnf Α ◽  
The Impact

In patients with obesity and diabetes mellitus, abnormal production of inflammatory factors may result in cardiovascular dysfunction. In the current study, we tested the impact of CD1d-mediated innate immune responses on the expression and activation of NFκB in the hearts of adipose diabetic ( db/db) mice. Splenocytes from adult db/db and CD1d-knockout mice of both genders and their wild-type, C57BL/6 and Balb/C counterparts were examined for tumor necrosis factor (TNF)-α and TNF-α receptor type 1. The percentage of natural killer T (NKT) cells in CD3+ T cells was compared with that in nondiabetic control mice. Despite the absence of inflammatory infiltrates, the hearts of db/db mice showed alterations in TNF-α receptor-1 and NFκB activity, including increased expression of both the NFκB p52 and p65 subunits. In the hearts of CD1d-knockout mice, p52 expression was reduced, while p65 expression remained largely unchanged. On echocardiography, the ratio of E to A transmitral flow velocities (an indicator of diastolic function) was significantly decreased in db/db mice after they swam for 30 minutes. These results provide evidence for CD1d-mediated NFκB activation and diastolic dysfunction in the hearts of db/db mice. Therefore, CD1d-associated abnormalities of innate immune responses and TNF-α production in splenic tissue may contribute to NFκB activation and cardiac dysfunction in type 2 diabetes.

LIR9, an immunoglobulin-superfamily–activating receptor, is expressed as a transmembrane and as a secreted molecule

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1484-1486 ◽  
Author(s):  
Luis Borges ◽  
Marek Kubin ◽  
Tracy Kuhlman
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Calcium Flux ◽  
Immunoglobulin Superfamily ◽  
Innate Immune Responses ◽  
Transmembrane Region ◽  
Tnf Α ◽  
Membrane Bound ◽  
Factor Α ◽  
Necrosis Factor

LIRs are immunoglobulinlike receptors that have activating and inhibitory functions in leukocytes. Here we report the identification of the first LIR family member, LIR9, expressed as a membrane-bound receptor and as a secreted molecule. We identified 4 different forms of LIR9, 2 of which encode transmembrane molecules and 2 encode secreted molecules. The transmembrane forms of LIR9 contain a short cytoplasmic domain and a charged arginine residue within the transmembrane region that is likely to mediate its association with another coreceptor. LIR9 is mostly expressed in myeloid cells, including monocytes and neutrophils. Cross-linking of LIR9 on the surfaces of monocytes induces calcium flux and secretion of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, indicating that LIR9 could play a role in triggering innate immune responses.

scholarly journals Differential Expression of Genes Related to Innate Immune Responses in Ex Vivo Spinal Cord and Cerebellar Slice Cultures Infected with West Nile Virus

2018 ◽  
Vol 9 (1) ◽  
pp. 1 ◽  
Author(s):  
Parminder Vig ◽  
Deyin Lu ◽  
Amber Paul ◽  
Ram Kuwar ◽  
Maria Lopez ◽  
...  
Keyword(s):  
Spinal Cord ◽  
West Nile Virus ◽  
Immune Responses ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Cell Types ◽  
Innate Immune ◽  
Slice Culture ◽  
Innate Immune Responses ◽  
West Nile

West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While neurons are a main target of WNV, other cell types, especially astrocytes, play an important role in promoting WNV-mediated central nervous system (CNS) damage. Conversely, it has been shown that cultured primary astrocytes secrete high levels of interferons (IFNs) immediately after WNV exposure to protect neighboring astrocytes, as well as neurons. However, how intrinsic responses to WNV in specific cell types and different regions of the brain modify immune protection is not fully understood. Here, we used a mouse ex vivo spinal cord slice culture (SCSC) and cerebellar slice culture (CSC) models to determine the innate immune responses specific to the CNS during WNV infection. Slices were prepared from the spinal cord and cerebellar tissue of 7–9-day-old mouse pups. Four-day-old SCSC or CSC were infected with 1 × 103 or 1 × 105 PFU of WNV, respectively. After 12 h exposure to WNV and 3 days post-infection in normal growth media, the pooled slice cultures were processed for total RNA extraction and for gene expression patterns using mouse Affymetrix arrays. The expression patterns of a number of genes were significantly altered between the mock- and WNV-treated groups, both in the CSCs and SCSCs. However, distinct differences were observed when CSC data were compared with SCSC. CSCs showed robust induction of interferons (IFNs), IFN-stimulated genes (ISGs), and regulatory factors. Some of the antiviral genes related to IFN were upregulated more than 25-fold in CSCs as compared to mock or SCSC. Though SCSCs had twice the number of dysregulated genes, as compared CSCs, they exhibited a much subdued IFN response. In addition, SCSCs showed astrogliosis and upregulation of astrocytic marker genes. In sum, our results suggest that early anti-inflammatory response to WNV infection in CSCs may be due to large population of distinct astrocytic cell types, and lack of those specialized astrocytes in SCSC may make spinal cord cells more susceptible to WNV damage. Further, the understanding of early intrinsic immune response events in WNV-infected ex vivo culture models could help develop potential therapies against WNV.

scholarly journals Effect of 6 weeks aerobic training on peripheral neuropathic pain and expression of NOTCH1 pathway genes in posterior spinal cord of diabetic male rats

2019 ◽  
Author(s):  
Siros Hosseini Askarabadi ◽  
Rahim Mirnasouri ◽  
Masoud Rahmati
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Aerobic Exercise ◽  
Aerobic Training ◽  
Training Group ◽  
Male Rats ◽  
Control Group ◽  
Factors Affecting ◽  
Glucose Levels

Introdution: Neuropathic pain is one of the most important factors affecting the quality of life of people with diabetes mellitus; regular exercises may have a role in reducing the pain associated with diabetes. The purpose of this study was the effect of six weeks aerobic training on environmental neuropathic pain and expression of the NOTCH1 pathway in the spinal cord of diabetic male rats. Methods: 40 male Wistar rats (age: 8 weeks old; weight 220-250g) were randomly divided into 4 groups: diabetic neuropathy training (DNT), diabetic neuropathy control (DNC), healthy training (HT) and healthy control (HC).The diabetic groups were induced by intraperitoneal injection of streptozotocin (STZ) and two weeks after induction of diabetes, behavioral pain tests were administered and endurance training protocol was performed for 6 weeks and 5 sessions per week. .The data were analyzed via  SPSS software version 19 and one-way ANOVA with a significant level (P <0.05) Results: After 6 weeks of aerobic training, the expression of NOTCH1 HES1 and il6 genes in diabetic neuropathy training group was significantly lower than the diabetic neuropathy control group (P≤0/05). The mean weight of the diabetic neuropathic training group was more than the diabetic neuropathy control group (p=0/001). Also, exercise significantly decreased blood glucose levels in the diabetic neuropathy group (P=0/237). Conclusion: It seems that aerobic exercise on rats with diabetic neuropathy can affect on pain sensation as well as the levels of NOTCH1, HES1 and il6 factors, and aerobic exercise is a suitable method for preventing, controlling and treating pain associated with diabetes.

scholarly journals Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

2013 ◽  
Vol 81 (8) ◽  
pp. 2686-2696 ◽  
Author(s):  
Komi Gbédandé ◽  
Stefania Varani ◽  
Samad Ibitokou ◽  
Parfait Houngbegnon ◽  
Sophie Borgella ◽  
...  
Keyword(s):  
Immune Responses ◽  
Early Life ◽  
In Utero ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Content Type ◽  
Cytokine Responses ◽  
Increased Risk ◽  
Tnf Α

ABSTRACTProtection from infections in early life relies extensively on innate immunity, but it is unknown whether and how maternal infections modulate infants' innate immune responses, thereby altering susceptibility to infections.Plasmodium falciparumcauses pregnancy-associated malaria (PAM), and epidemiological studies have shown that PAM enhances infants' susceptibility to infection withP. falciparum. We investigated how PAM-mediated exposuresin uteroaffect innate immune responses and their relationship with infection in infancy. In a prospective study of mothers and their babies in Benin, we investigated changes in Toll-like receptor (TLR)-mediated cytokine responses related toP. falciparuminfections. Whole-blood samples from 134 infants at birth and at 3, 6, and 12 months of age were stimulated with agonists specific for TLR3, TLR4, TLR7/8, and TLR9. TLR-mediated interleukin 6 (IL-6) and IL-10 production was robust at birth and then stabilized, whereas tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses were weak at birth and then increased. In multivariate analyses, maternalP. falciparuminfections at delivery were associated with significantly higher TLR3-mediated IL-6 and IL-10 responses in the first 3 months of life (P< 0.05) and with significantly higher TLR3-, TLR7/8-, and TLR9-mediated TNF-α responses between 6 and 12 months of age (P< 0.05). Prospective analyses showed that higher TLR3- and TLR7/8-mediated IL-10 responses at birth were associated with a significantly higher risk ofP. falciparuminfection in infancy (P< 0.05). Neonatal and infant intracellular TLR-mediated cytokine responses are conditioned byin uteroexposure through PAM late in pregnancy. Enhanced TLR-mediated IL-10 responses at birth are associated with an increased risk ofP. falciparuminfection, suggesting a compromised ability to combat infection in early life.

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