scholarly journals MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock

2005 ◽  
Vol 203 (1) ◽  
pp. 131-140 ◽  
Author(s):  
Qun Zhao ◽  
Xianxi Wang ◽  
Leif D. Nelin ◽  
Yongxue Yao ◽  
Ranyia Matta ◽  
...  
Keyword(s):  
Map Kinase ◽  
Endotoxic Shock ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Kinase Activation ◽  
Lps Challenge ◽  
Map Kinase Phosphatase ◽  
Tnf Α ◽  
Severe Hypotension

Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1−/− cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.

scholarly journals MAP Kinase Phosphatase-1 Protects against Inflammatory Bone Loss

2009 ◽  
Vol 88 (12) ◽  
pp. 1125-1130 ◽  
Author(s):  
R. Sartori ◽  
F. Li ◽  
K.L. Kirkwood
Keyword(s):  
Bone Loss ◽  
Map Kinase ◽  
Map Kinases ◽  
Group Analysis ◽  
P38 Map Kinase ◽  
Wild Type ◽  
Map Kinase Phosphatase ◽  
Tnf Α ◽  
Protein Map ◽  
Mitogen Activated Protein

The mitogen-activated protein (MAP) kinase phosphatase (MKP) family plays an important function in regulating the pro-inflammatory cytokines by deactivating MAP kinases. MKP-1 is essential for the dephosphorylation of p38 MAP kinase that regulates expression of IL-6, TNF-α, and IL-1β. We hypothesized that MKP-1 regulates inflammatory bone loss in experimental periodontitis. Wild-type and Mkp-1−/− mice received A. actinomycetemcomitans LPS injection in the palatal region or PBS control 3 times/wk for 30 days. Mice were killed, and maxillae were assessed by microcomputed tomography, histological analysis, and TRAP staining for measurement of bone loss, extent of inflammation, and degree of osteoclastogenesis. Results indicated that, in LPS-injected Mkp-1−/− mice, significantly greater bone loss occurred with more inflammatory infiltrate and a significant increase in osteoclastogenesis compared with Mkp-1−/− control sites or either wild-type group. Analysis of these data indicates that MKP-1 plays a key role in the regulation of inflammatory bone loss.

scholarly journals Regulation of Pulmonary and Systemic Bacterial Lipopolysaccharide Responses in Transgenic Mice Expressing Human Elafin

2003 ◽  
Vol 71 (7) ◽  
pp. 3766-3774 ◽  
Author(s):  
J.-M. Sallenave ◽  
G. A. Cunningham ◽  
R. M. James ◽  
G. McLachlan ◽  
C. Haslett
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Bacterial Lipopolysaccharide ◽  
Dual Function ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Elastase Inhibitor ◽  
Tnf Α

ABSTRACT The control of lung inflammation is of paramount importance in a variety of acute pathologies, such as pneumonia, the acute respiratory distress syndrome, and sepsis. It is becoming increasingly apparent that local innate immune responses in the lung are negatively influenced by systemic inflammation. This is thought to be due to a local deficit in cytokine responses by alveolar macrophages and neutrophils following systemic bacterial infection and the development of a septic response. Recently, using an adenovirus-based strategy which overexpresses the human elastase inhibitor elafin locally in the lung, we showed that elafin is able to prime lung innate immune responses. In this study, we generated a novel transgenic mouse strain expressing human elafin and studied its response to bacterial lipopolysaccharide (LPS) when the LPS was administered locally in the lungs and systemically. When LPS was delivered to the lungs, we found that mice expressing elafin had lower serum-to-bronchoalveolar lavage ratios of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein 2, and monocyte chemoattractant protein 1, than wild-type mice. There was a concomitant increase in inflammatory cell influx, showing that there was potential priming of innate responses in the lungs. When LPS was given systemically, the mice expressing elafin had reduced levels of serum TNF-α compared to the levels in wild-type mice. These results indicate that elafin may have a dual function, promoting up-regulation of local lung innate immunity while simultaneously down-regulating potentially unwanted systemic inflammatory responses in the circulation.

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 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

2019 ◽  
Vol 131 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Wenling Jian ◽  
Lili Gu ◽  
Brittney Williams ◽  
Yan Feng ◽  
Wei Chao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Innate Immune ◽  
Organ Injury ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

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 Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0247738
Author(s):  
Daniel Schnepf ◽  
Pedro Hernandez ◽  
Tanel Mahlakõiv ◽  
Stefania Crotta ◽  
Meagan E. Sullender ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Innate Immune ◽  
Fine Tuning ◽  
Type I ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Interleukin 22 ◽  
Commensal Microbiota ◽  
Type Iii Interferon ◽  
Deficient Mice

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

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.

Innate inflammatory and phagocytic responses to Plasmodium falciparum: linked processes or molecularly discrete pathways?s

2007 ◽  
Vol 30 (4) ◽  
pp. 81
Author(s):  
Laura Erdman ◽  
Gabriela Cosio ◽  
Samir N. Patel ◽  
Sergio Grinstein ◽  
Kevin C. Kain
Keyword(s):  
Severe Malaria ◽  
Scavenger Receptor ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Blood Stage Infection ◽  
Representative Model ◽  
Pre Treatment ◽  
Stage Infection

Background: Effective innate immune responses are important for control of malaria blood-stage infection and in preventing progression to severe malaria in non-immune individuals. Key innate defenses include a tightly regulated inflammatory response and host clearance of parasitized erythrocytes (PE). Pattern recognition receptors on macrophages mediate these processes: parasite glycosylphosphatidylinositol (GPI) activates TLR2 to induce inflammation – an excess of which is associated with severe malaria – while scavenger receptor CD36 mediates non-opsonic uptake of PEs. Both pathways are potential therapeutic targets, but it is unclear whether they are interdependent. Findings in other systems implicate CD36 in inflammation and TLR2 in phagocytosis, and recent evidence indicates that CD36 and TLR2 can directly cooperate. Methods: We investigated whether the innate inflammatory and phagocytic responses of macrophages to P. falciparum are separable: does CD36-mediated PE internalization have inflammatory outcomes, and does TLR2 regulate PE uptake? CD36-mediated endocytosis failed to induce TNFα production. As a more representative model of innate PE uptake, α-CD36 EBABs (Erythrocyte-Biotin-Avidin-Biotinylated antibody) were generated; macrophages internalized EBABs in a CD36-specific manner via a signaling pathway similar to that of PE uptake. Results: Compared to controls, neither PE nor EBAB internalization induced TNFα release, indicating that the inflammatory consequences of CD36 engagement are ligand dependent. Regarding TLR2 regulation of PE uptake, wild type and Tlr2-/- macrophages showed no differences in EBAB or PE uptake. Pre-treatment of macrophages with P. falciparum GPI enhanced EBAB internalization, but this effect was CD36-independent and generalizable to other TLR ligands. Conclusions: These results suggest that innate inflammatory and phagocytic responses of macrophages to malaria are discrete. Thus, therapeutic augmentation of CD36-mediated PE uptake should not exacerbate inflammation, nor should inhibition of the TLR2 pathway compromise CD36-mediated PE clearance. The role of TLR-enhanced internalization in malaria will be further examined.

scholarly journals Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome

2018 ◽  
Vol 1 (6) ◽  
pp. e201800237 ◽  
Author(s):  
Connie Ross ◽  
Amy H Chan ◽  
Jessica Von Pein ◽  
Dave Boucher ◽  
Kate Schroder
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Endotoxic Shock ◽  
Innate Immune ◽  
Order Structure ◽  
Gram Negative Bacteria ◽  
Innate Immune Responses ◽  
Protease Activation ◽  
Necessary And Sufficient ◽  
Active Caspase

Caspase-11 is a cytosolic sensor and protease that drives innate immune responses to the bacterial cell wall component, LPS. Caspase-11 provides defence against cytosolic Gram-negative bacteria; however, excessive caspase-11 responses contribute to murine endotoxic shock. Upon sensing LPS, caspase-11 assembles a higher order structure called the non-canonical inflammasome that enables the activation of caspase-11 protease function, leading to gasdermin D cleavage and cell death. The mechanism by which caspase-11 acquires protease function is, however, poorly defined. Here, we show that caspase-11 dimerization is necessary and sufficient for eliciting basal caspase-11 protease function, such as the ability to auto-cleave. We further show that during non-canonical inflammasome signalling, caspase-11 self-cleaves at site (D285) within the linker connecting the large and small enzymatic subunits. Self-cleavage at the D285 site is required to generate the fully active caspase-11 protease (proposed here to be p32/p10) that mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production. This study provides a detailed molecular mechanism by which LPS induces caspase-11–driven inflammation and cell death to provide host defence against cytosolic bacterial infection.

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