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.

Role of the myeloid differentiation primary response (MYD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) pathways in dengue

Life Sciences ◽  
2016 ◽  
Vol 162 ◽  
pp. 33-40 ◽  
Author(s):  
Anyelo Duran ◽  
Nereida Valero ◽  
Jesus Mosquera ◽  
Lineth Delgado ◽  
Melchor Alvarez-Mon ◽  
...  
Keyword(s):  
Primary Response ◽  
Myeloid Differentiation ◽  
Interferon Β ◽  
Tir Domain

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 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 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.

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 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 Developmental retrotransposon activation primes host immunity for future viral-clearance

2020 ◽  
Author(s):  
Lu Wang ◽  
Lauren Tracy ◽  
ZZ Zhao Zhang
Keyword(s):  
Innate Immune System ◽  
Rare Event ◽  
Pupal Stage ◽  
Host Immunity ◽  
Viral Clearance ◽  
Innate Immune ◽  
Immune Priming ◽  
Physiological Conditions ◽  
Term Benefit

AbstractTransposons are thought to be largely suppressed under physiological conditions, ensuring that their mobilization is a rare event. By tracking mobilization, we show that during metamorphosis at the Drosophila pupal stage, the Gypsy retrotransposon selectively mobilizes in regenerating tissues. In the newly formed tissues, this wave of Gypsy activation primes the host’s innate immune system by inducing the production of antimicrobial peptides (AMPs). Moreover, early immune-priming functions of Gypsy are essential for combating viral invasion in adult flies: flies with Gypsy being silenced at the pupal stage are unable to clear viruses and succumb to viral infection. Our data reveal that regulated activation of transposons during animal developmental endows a long-term benefit in pathogen warfare.

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