scholarly journals Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Maria Inês Cunha ◽  
Minhui Su ◽  
Ludovico Cantuti-Castelvetri ◽  
Stephan A. Müller ◽  
Martina Schifferer ◽  
...  
Keyword(s):  
Primary Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Immune System Function ◽  
Tnf Α ◽  
Inflammatory Activation ◽  
Myelin Debris ◽  
Inflammation Resolution ◽  
Myelin Injury ◽  
Deficient Mice

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB–dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.

scholarly journals Possible Involvement of MyD88 in Regulating Stress Response in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Toru Hosoi ◽  
Yosuke Yamawaki ◽  
Hitomi Kimura ◽  
Shoko Honda ◽  
Koichiro Ozawa
Keyword(s):  
Stress Response ◽  
Immobilization Stress ◽  
Forced Swim Test ◽  
Primary Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Adapter Protein ◽  
Immobility Time ◽  
Deficient Mice

Myeloid differentiation primary response 88 (MyD88) is an adapter protein of the toll-like receptor (TLR) family that regulates innate immune function. Here, we identified a novel role of MyD88 in regulating stress response. MyD88 deficiency decreased immobility time in the forced swim test without affecting locomotor activity in mice. Immobilization stress-induced production of serum corticosterone was also completely inhibited by MyD88 deficiency. Stress induced decrease in glucocorticoid receptor in the hippocampus. On the other hand, stress exposure in MyD88 deficient mice did not cause decrease in its level in the hippocampus. Furthermore, immobilization stress-induced reduction of brain-derived neurotrophic factor (BDNF) levels in the hippocampus was ameliorated by MyD88 deficiency. These results suggest that MyD88 deficiency attenuates depression-like behavior by regulating corticosterone and BDNF levels. Overall, these results indicate the key role of MyD88 in regulating stress response in mice.

scholarly journals SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease

2019 ◽  
Vol 216 (4) ◽  
pp. 743-756 ◽  
Author(s):  
Caihong Zhu ◽  
Bei Li ◽  
Karl Frontzek ◽  
Yingjun Liu ◽  
Adriano Aguzzi
Keyword(s):  
Immune Responses ◽  
Prion Disease ◽  
Neuronal Apoptosis ◽  
Microglial Activation ◽  
Axonal Degeneration ◽  
Primary Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Innate Immune Responses ◽  
Whole Transcriptome

SARM1 (sterile α and HEAT/armadillo motif–containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.

scholarly journals FSTL1 aggravates sepsis-induced acute kidney injury through regulating TLR4/MyD88/NF-κB pathway in newborn rats

2021 ◽  
Keyword(s):  
Acute Kidney Injury ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Newborn Rats ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Tnf Α ◽  
Hematoxylin Eosin

Background: The aim of this work was to investigate whether Follistatin like 1 (FSTL1) exerted an effect on acute kidney injury (AKI) induced by sepsis, and to explore the molecular mechanism. Methods: A cecal ligation and puncture (CLP) model was established and adenoviral solution was administrated to newborn rats to achieve FSTL1 knockdown. Colorimetric assays measured concentrations of serum creatinine and blood urea nitrogen (BUN) and ELISA assays were performed to examine TNF-α, IL-1β and IL-6 levels in serum and kidney tissues. Kidney histological analysis was performed using hematoxylin-eosin (HE) staining. Protein levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated p65 (p-p65) and total p65 (p65) were determined by western blotting. Results: FSTL1 was significantly up-regulated in kidneys following CLP, but subsequent FSTL1 inhibition alleviated AKI. FSTL1 knockdown following CLP inhibited the production of TNF-α, IL-1β, IL-6 and inactivated the TLR4/MyD88/NF-κB pathway. Furthermore, FSTL1 overexpression activated the TLR4/MyD88/NF-κB pathway following CLP, but TLR4 inhibitor TAK242 abolished this effect. Conclusions: FSTL1 aggravates sepsis-induced acute kidney injury through regulating the TLR4/MyD88/NF-κB pathway.

scholarly journals MYCOBACTERIUM TUBERCULOSIS SISTEM IMUN ALAMIAH TERKAIT PENERIMANYA

2016 ◽  
Vol 19 (1) ◽  
pp. 45
Author(s):  
Jusak Nugraha
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokine ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Protective Function ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Myeloid Differentiation Factor

Various attemp to investigate immune response towards tuberculosis has been done in order to eradicate or to make vaccination against tuberculosis (TB) effectively. Recently it is known that innate immunity has an important role in immunity to TB despite adaptive immune response, because it was proved that adaptive immune response alone was not sufficient to eradicate this microorganism thoroughly and completely in patient’s body. After Toll-Like Receptor (TLR) was found in the end of the 20th century, many progresses has been obtained in understanding about the activation of this innate immune response. But it is still needed to understand more deeply in the immune response to M. tuberculosis to lead the development of therapy or vaccination that bring into more precise target. The activation through TLR by parts of Mycobacterium induce cytoplasm protein adaptor MyD88 (Myeloid Differentiation factor 88). MyD88 has the function to activate NF- κB and secrete pro-inflammatory cytokine such as TNF-α, IL-6, IL-12. Involvement of MyD88 is not solely dependent of TLR2 receptor and there are another pathways to induce protective function of immunocompetent cells in TB.

TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Garyfallia Gouna ◽  
Christian Klose ◽  
Mar Bosch-Queralt ◽  
Lu Liu ◽  
Ozgun Gokce ◽  
...  
Keyword(s):  
Er Stress ◽  
Lipid Droplet ◽  
Metabolic Pathways ◽  
Lipid Droplets ◽  
Signal Propagation ◽  
Innate Immune ◽  
Protective Response ◽  
Regenerative Response ◽  
Myelin Debris ◽  
Deficient Mice

Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.

Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases

2015 ◽  
Vol 26 (4) ◽  
Author(s):  
Wang Xiang ◽  
Zhang-Yong Chao ◽  
Du-Yi Feng
Keyword(s):  
Intracellular Signaling ◽  
Adaptor Proteins ◽  
Primary Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Intracellular Signaling Pathways ◽  
Primary Response Gene ◽  
Myd88 Signaling

AbstractToll-like receptors (TLRs) are important innate immune proteins, and the activation of the TLRs results in the activation of intracellular signaling pathways, leading to the expression of proinflammatory cytokines that are essential to the identification and clearance of invading pathogens. TLR signaling occurs through adaptor proteins, most commonly myeloid differentiation primary response gene 88 (

scholarly journals TLRs in COVID-19: How they drive immunopathology and the rationale for modulation

2021 ◽  
pp. 175342592110513
Author(s):  
F. Linzee Mabrey ◽  
Eric D Morrell ◽  
Mark M Wurfel
Keyword(s):  
Innate Immune System ◽  
Primary Response ◽  
Viral Clearance ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Tir Domain ◽  
Critical Elements ◽  
Severity Of Disease ◽  
Viral Illness ◽  
Myd88 Pathway

COVID-19 is both a viral illness and a disease of immunopathology. Proximal events within the innate immune system drive the balance between deleterious inflammation and viral clearance. We hypothesize that a divergence between the generation of excessive inflammation through over activation of the TLR associated myeloid differentiation primary response (MyD88) pathway relative to the TIR-domain-containing adaptor-inducing IFN-β (TRIF) pathway plays a key role in COVID-19 severity. Both viral elements and damage associated host molecules act as TLR ligands in this process. In this review, we detail the mechanism for this imbalance in COVID-19 based on available evidence, and we discuss how modulation of critical elements may be important in reducing severity of disease.

scholarly journals SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease

2018 ◽  
Author(s):  
Caihong Zhu ◽  
Bei Li ◽  
Karl Frontzek ◽  
Yingjun Liu ◽  
Adriano Aguzzi
Keyword(s):  
Immune Responses ◽  
Prion Disease ◽  
Wallerian Degeneration ◽  
Microglial Activation ◽  
Axonal Degeneration ◽  
Primary Response ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Innate Immune Responses ◽  
Whole Transcriptome

AbstractSARM1 (sterile α and HEAT/armadillo motifs containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of proapoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration, and suggest that XAF1 might constitute a therapeutic target in prion disease.

scholarly journals Delineating the Requirement for the Borrelia burgdorferi Virulence Factor OspC in the Mammalian Host

2006 ◽  
Vol 74 (6) ◽  
pp. 3547-3553 ◽  
Author(s):  
Philip E. Stewart ◽  
Xiaohui Wang ◽  
Dawn M. Bueschel ◽  
Dawn R. Clifton ◽  
Dorothee Grimm ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Physiological Role ◽  
Surface Protein ◽  
Protective Role ◽  
Innate Immune ◽  
Myeloid Differentiation ◽  
Mammalian Host ◽  
Mammalian Infection ◽  
Deficient Mice

ABSTRACT We previously demonstrated that outer surface protein C (OspC) of Borrelia burgdorferi is essential for establishing mammalian infection. However, the role of OspC in mammalian infection is unknown. Here, we report experiments designed to distinguish between two models of OspC function in the mammalian host: (i) OspC fulfills an essential physiological role for growth and host adaptation or (ii) OspC provides a protective role for evasion of components of the innate immune response. We found that a B. burgdorferi ospC mutant, previously demonstrated to be noninfectious in both immunocompetent and SCID mice, could survive in the relatively immune-privileged environment of dialysis membrane chambers implanted within the peritoneum of a rat. The ospC mutant also adapts to the mammalian environment, as determined by the protein profiles of the chamber-cultivated spirochetes. Therefore, OspC does not appear to provide a physiological function for the survival of B. burgdorferi within the mammalian host. The second model, evasion of the innate immune system, was tested by assessing the infectivity of the ospC mutant in mice deficient for myeloid differentiation protein 88 (MyD88). Recent studies have shown that B. burgdorferi is prevented from reaching high cell numbers in the mammalian host by MyD88-dependent signaling pathways. The ospC mutant was incapable of infecting MyD88-deficient mice, suggesting that the role of OspC cannot be related solely to evasion of MyD88-mediated innate immunity. These results reiterate the importance of OspC in mammalian infection and eliminate simple models of function for this enigmatic protein.

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