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 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.

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 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.

Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis

2014 ◽  
Vol 81 (4) ◽  
pp. 320-324 ◽  
Author(s):  
Sonia Nasi ◽  
Hang-Korng Ea ◽  
Véronique Chobaz ◽  
Peter van Lent ◽  
Frédéric Lioté ◽  
...  
Keyword(s):  
Murine Model ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Toll Like Receptors ◽  
Response Gene ◽  
Primary Response Gene

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Differential Role of MyD88 in Macrophage-Mediated Responses to Opportunistic Fungal Pathogens

2003 ◽  
Vol 71 (9) ◽  
pp. 5280-5286 ◽  
Author(s):  
Kieren A. Marr ◽  
S. Arunmozhi Balajee ◽  
Thomas R. Hawn ◽  
Adrian Ozinsky ◽  
Uyenvy Pham ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Cytokine Production ◽  
Pathogenic Fungi ◽  
Adapter Protein ◽  
Wild Type ◽  
Intracellular Killing ◽  
Pathogenic Yeast ◽  
Myd88 Signaling ◽  
Deficient Mice

ABSTRACT Toll-like receptors mediate macrophage recognition of microbial ligands, inducing expression of microbicidal molecules and cytokines via the adapter protein MyD88. We investigated the role of MyD88 in regulating murine macrophage responses to a pathogenic yeast (Candida albicans) and mold (Aspergillus fumigatus). Macrophages derived from bone marrow of MyD88-deficient mice (MyD88−/−) demonstrated impaired phagocytosis and intracellular killing of C. albicans compared to wild-type (MyD88+/+) macrophages. In contrast, ingestion and killing of A. fumigatus conidia was MyD88 independent. Cytokine production by MyD88−/− macrophages in response to C. albicans yeasts and hyphae was substantially decreased, but responses to A. fumigatus hyphae were preserved. These results provide evidence that MyD88 signaling is involved in phagocytosis and killing of live C. albicans, but not A. fumigatus. The differential role of MyD88 may represent one mechanism by which macrophages regulate innate responses specific to different pathogenic fungi.

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 Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.

1993 ◽  
Vol 13 (2) ◽  
pp. 841-851 ◽  
Author(s):  
K A Lord ◽  
A Abdollahi ◽  
B Hoffman-Liebermann ◽  
D A Liebermann
Keyword(s):  
Transcription Factors ◽  
Leucine Zipper ◽  
Culture Media ◽  
Terminal Differentiation ◽  
Cell Types ◽  
Primary Response ◽  
Myeloid Differentiation ◽  
Active Transcription

The proto-oncogenes c-jun, junB, junD, and c-fos recently have been shown to encode for transcription factors with a leucine zipper that mediates dimerization to constitute active transcription factors; juns were shown to dimerize with each other and with c-fos, whereas fos was shown to dimerize only with juns. After birth, hematopoietic cells of the myeloid lineage, and some other terminally differentiated cell types, express high levels of c-fos. Still, the role of fos/jun transcription factors in normal myelopoiesis or in leukemogenesis has not been established. Recently, c-jun, junB, and junD were identified as myeloid differentiation primary response genes stably expressed following induction of terminal differentiation of myeloblastic leukemia M1 cells. Intriguingly, c-fos, though induced during normal myelopoiesis, was not induced upon M1 differentiation. To gain further insights into the role of fos/jun in normal myelopoiesis and leukemogenicity, M1fos and M1junB cell lines, which constitutively express c-fos and junB, respectively, were established. It was shown that enforced expression of c-fos, and to a lesser extent junB, in M1 cells results in both an increased propensity to differentiate and a reduction in the aggressiveness of the M1 leukemic phenotype. M1fos cells constitutively expressed immediate-early and late genetic markers of differentiated M1 cells. The in vitro differentiation of normal myeloblasts into mature macrophages and granulocytes, as well as the increased propensity of M1fos leukemic myeloblasts to be induced for terminal differentiation, was dramatically impaired with use of c-fos antisense oligomers in the culture media. Taken together, these observations show that the proto-oncogenes which encode for fos/jun transcription factors play important roles in promoting myeloid differentiation. The ability of the M1 leukemic myeloblasts to be induced for terminal differentiation in the absence of apparent fos expression indicates that there is some redundancy among the fos/jun family of transcription factors in promoting myeloid differentiation; however, juns alone cannot completely compensate for the lack of fos. Thus, genetic lesions affecting fos/jun expression may play a role in the development of "preleukemic" myelodysplastic syndromes and their further progression to leukemias.

NLRP10-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4113-4113
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Red Blood Cells ◽  
T Cell Activation ◽  
Blood Cells ◽  
Cell Activation ◽  
Innate Immune ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. Every non-autologous red cell unit has multiple antigens foreign to the transfused recipient; some people respond to these foreign antigens with an adaptive immune response and some do not. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused red blood cells. A particularly useful transgenic “HOD mouse” has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffybblood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the NOD-like receptor NLRP10 fail to develop alloimmunity to transfused red blood cells. Surprisingly, the early innate immune cytokine response, including IL-6, IL-1beta and TNF-alpha, was unaffected in mice lacking NLRP10. Yet both B cell and T cell activation in the spleen to the transgenic transfused RBCs was abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in NLRP10-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. We have previously demonstrated that NLRP10-deficient dendritic cells fail to migrate from peripheral tissues such as the skin to draining lymph nodes. Our preliminary data now suggest that NLRP10-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The relative role of dendritic cells, B cells and macrophages in the induction of erythrocyte alloimmunization remain unclear. Further, the need for DC migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed. These mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion in NLRP10-deficient mice and the specific role of splenic dendritic cells in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

Role of TLR2, TLR4, and MyD88 in murine ozone-induced airway hyperresponsiveness and neutrophilia

2007 ◽  
Vol 103 (4) ◽  
pp. 1189-1195 ◽  
Author(s):  
Alison S. Williams ◽  
Sum-Yee Leung ◽  
Puneeta Nath ◽  
Nadia M. Khorasani ◽  
Pankaj Bhavsar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Airway Hyperresponsiveness ◽  
Myeloid Differentiation ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Toll Like Receptor ◽  
Inflammatory Gene Expression ◽  
Keratinocyte Chemoattractant ◽  
Myeloid Differentiation Factor

Exposure to air pollutants such as ozone (O3) induces airway hyperresponsiveness (AHR) and airway inflammation. Toll-like receptors (TLR) are first-line effector molecules in innate immunity to infections and signal via adapter proteins, including myeloid differentiation factor-88 (MyD88). We investigated the sensing of ozone by TLR2, TLR4, and MyD88. Ozone induced AHR in wild-type (WT) C57BL/6 mice, but AHR was absent in TLR2−/−, TLR4−/−, and MyD88−/− mice. Bronchoalveolar lavage neutrophilia induced by ozone was inhibited at 3 h but not at 24 h in TLR2−/− and TLR4−/− mice, while in MyD88−/− mice, this was inhibited at 24 h. We investigated the expression of inflammatory cytokines and TLR2, TLR4, and MyD88 in these mice. Ozone induced time-dependent increases in inflammatory gene expression of keratinocyte chemoattractant (KC) and IL-6 and of TLR2, TLR4, and MyD88 in WT mice. IL-6 and KC expression induced by ozone was inhibited in TLR2−/−, TLR4−/−, and MyD88−/− mice. Expression of MyD88 was increased in TLR2−/− and TLR4−/− mice, while induction of TLR2 or TLR4 was reduced in TLR2−/− and TLR4−/− mice, respectively. TLR2 and TLR4 mediate AHR induced by oxidative stress such as ozone, while the adapter protein MyD88, but not TLR2 or TLR4, is important in mediating ozone-induced neutrophilia. TLR2 and TLR4 may also be important in regulating the speed of neutrophilic response. Therefore, ozone may induce murine AHR and neutrophilic inflammation through the activation of the Toll-like receptor pathway that may sense noninfectious stimuli such as oxidative stress.

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