scholarly journals Inhibition of TLR4 Signaling Protects Mice From Sensory and Motor Dysfunction in an Animal Model of Autoimmune Peripheral Neuropathy

2021 ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Mu Yang ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
Peripheral Neuropathy ◽  
T Cell Activation ◽  
Peripheral Nerves ◽  
Drug Target ◽  
Cell Activation ◽  
Disease Onset ◽  
Intraperitoneal Administration ◽  
Motor Dysfunction ◽  
Autoimmune Neuropathy ◽  
Molecular Patterns

Abstract BackgroundWhile the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain Barre Syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. MethodsAPN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. ResultsTLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8 + T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. ConclusionThe study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

scholarly journals Inhibition of TLR4 signaling protects mice from sensory and motor dysfunction in an animal model of autoimmune peripheral neuropathy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Mu Yang ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
Peripheral Neuropathy ◽  
T Cell Activation ◽  
Peripheral Nerves ◽  
Drug Target ◽  
Disease Onset ◽  
Intraperitoneal Administration ◽  
Motor Dysfunction ◽  
Tlr4 Signaling ◽  
Autoimmune Neuropathy ◽  
Molecular Patterns

Abstract Background While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain-Barre syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. Methods APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. Results TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8+ T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. Conclusion The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

scholarly journals Interactions between tumor-derived proteins and Toll-like receptors

2020 ◽  
Vol 52 (12) ◽  
pp. 1926-1935
Author(s):  
Gun-Young Jang ◽  
Ji won Lee ◽  
Young Seob Kim ◽  
Sung Eun Lee ◽  
Hee Dong Han ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Tissue Injury ◽  
Suppressor Cells ◽  
Toll Like Receptors ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Dying Cells

AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.

scholarly journals Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV

2019 ◽  
Author(s):  
Nicolas Vabret ◽  
Valérie Najburg ◽  
Alexander Solovyov ◽  
Petr Šulc ◽  
Sreekumar Balan ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Rna Virus ◽  
Type I ◽  
Endogenous Ligands ◽  
Rna Triphosphatase ◽  
Molecular Patterns ◽  
Hiv 1

AbstractPattern recognition receptors (PRRs) protect against host invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. While microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation during viral infection remain overlooked. In this work, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary structure and its 5’-triphosphate extremity. Further, we found that HIV-1 infection triggers a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, leading to an increase of Y-RNA 5’-triphosphorylation that enables their immunogenicity. Importantly, we show that altering DUSP11 expression is sufficient to induce a type-I interferon and T cell activation transcriptional program associated with HIV-1 infection. Overall, our work uncovers the critical contribution of endogenous repeat RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.

scholarly journals CX3CR1 But Not CCR2 Expression Is Required for the Development of Autoimmune Peripheral Neuropathy in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
T Cells ◽  
Peripheral Neuropathy ◽  
Peripheral Nerves ◽  
Chemokine Receptors ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Potential Contribution ◽  
Ccr2 Expression ◽  
Compensatory Proliferation ◽  
T Cell Survival

One hallmark of Guillain-Barre syndrome (GBS), a prototypic autoimmune peripheral neuropathy (APN) is infiltration of leukocytes (macrophages and T cells) into peripheral nerves, where chemokines and their receptors play major roles. In this study, we aimed to understand the potential contribution of chemokine receptors CCR2 and CX3CR1 in APN by using a well-established mouse model, B7.2 transgenic (L31) mice, which possesses a predisposed inflammatory background. We crossbred respectively CCR2KO and CX3CR1KO mice with L31 mice. The disease was initiated by partial ligation on one of the sciatic nerves. APN pathology and neurological function were evaluated on the other non-ligated sciatic nerve/limb. Our results revealed that L31/CX3CR1KO but not L31/CCR2KO mice were resistant to APN. CX3CR1 is needed for maintaining circulating monocyte and CD8+ T cell survival. While migration of a significant number of activated CD8+ T cells to peripheral nerves is essential in autoimmune response in nerve, recruitment of monocytes into PNS seems optional. Disease onset is independent of CCR2 mediated blood-derived macrophage recruitment, which can be replaced by compensatory proliferation of resident macrophages in peripheral nerve. CX3CR1 could also contribute to APN via its critical involvement in maintaining nerve macrophage phagocytic ability. We conclude that blockade of CX3CR1 signaling may represent an interesting anti-inflammatory strategy to improve therapeutic management for GBS patients.

scholarly journals 2′-Hydroxycinnamaldehyde ameliorates imiquimod-induced psoriasiform inflammation by targeting PKM2-STAT3 signaling in mice

2021 ◽  
Author(s):  
Lihua Hao ◽  
Yuancheng Mao ◽  
Jin Park ◽  
Byoung-Mog Kwon ◽  
Eun Ju Bae ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Intraperitoneal Administration ◽  
Inflammatory Cells ◽  
Stem Bark ◽  
Skin Lesions ◽  
Stat3 Signaling ◽  
Anticancer Effects ◽  
Th17 Cell Differentiation ◽  
New Treatment

Abstract2′-Hydroxycinnamaldehyde (HCA), the active component isolated from the stem bark of Cinnamomum cassia, exerts anticancer effects through multiple mechanisms. We recently determined that HCA inhibits signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Because STAT3 overactivation has been closely associated with the development of psoriasis, a chronic autoimmune skin disease, we examined whether HCA ameliorates skin lesions in an imiquimod-induced psoriasis-like mouse model. The results showed that intraperitoneal administration of HCA alleviated imiquimod-induced psoriasis-like dermatitis, epidermal thickening, dermal infiltration of inflammatory cells, and proinflammatory cytokine production. Mechanistically, HCA inhibited pyruvate kinase isozyme M2 and STAT3 signaling, leading to the suppression of T cell activation, Th17 cell differentiation, and keratinocyte hyperproliferation. These results suggest that HCA may be a new treatment for psoriasis and other STAT3-mediated skin disorders, such as infection, inflammation and carcinogenesis.

scholarly journals Annexin-1 modulates T-cell activation and differentiation

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1095-1102 ◽  
Author(s):  
Fulvio D'Acquisto ◽  
Ahmed Merghani ◽  
Emilio Lecona ◽  
Guglielmo Rosignoli ◽  
Karim Raza ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Disease Onset ◽  
Etiologic Factor ◽  
Nuclear Factor ◽  
Th2 Response ◽  
Activated T Cells ◽  
Annexin 1

Abstract Annexin-1 is an anti-inflammatory protein that plays an important homeostatic role in innate immunity; however, its potential actions in the modulation of adaptive immunity have never been explored. Although inactive by itself, addition of annexin-1 to stimulated T cells augmented anti-CD3/CD28-mediated CD25 and CD69 expression and cell proliferation. This effect was paralleled by increased nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFATs), and activator protein-1 (AP-1) activation and preceded by a rapid T-cell receptor (TCR)–induced externalization of the annexin-1 receptor. Interestingly, differentiation of naive T cells in the presence of annexin-1 increased skewing in Th1 cells; in the collagen-induced arthritis model, treatment of mice with annexin-1 during the immunization phase exacerbated signs and symptoms at disease onset. Consistent with these findings, blood CD4+ cells from patients with rheumatoid arthritis showed a marked up-regulation of annexin-1 expression. Together these results demonstrate that annexin-1 is a molecular “tuner” of TCR signaling and suggest this protein might represent a new target for the development of drugs directed to pathologies where an unbalanced Th1/Th2 response or an aberrant activation of T cells is the major etiologic factor.

scholarly journals Tune Up In Situ Autovaccination against Solid Tumors with Oncolytic Viruses

2018 ◽  
Author(s):  
Teresa Nguyen ◽  
Naze G. Avci ◽  
Dong Ho Shin ◽  
Naiara Martinez-Velez ◽  
Hong Jiang
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Oncolytic Viruses ◽  
Molecular Patterns ◽  
Cell Inhibition ◽  
Damage Associated Molecular Patterns

With the progress of immunotherapy in cancer, oncolytic viruses (OVs) are getting more and more attention during the past decade. Due to their cancer-selective and immunogenic property, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, generating pathogen-associated molecular patterns (PAMPs) and danger (damage)-associated molecular patterns (DAMPs). These signals trigger innate immune response to modulate the solid tumor microenvironment, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. Here, we summarize the conceptual updates of oncolytic virotherapy, immunotherapy, and the strategies to enhance the virus-mediated anti-tumor immune response, including: 1. Arm OVs with cytokines to modulated innate and adaptive immunity; 2. Combine OVs with immune checkpoint inhibitors to release T cell inhibition; 3. Combine OVs with immune co-stimulators to enhance T cell activation.

scholarly journals Glutamine antagonism attenuates physical and cognitive deficits in a model of MS

2019 ◽  
Vol 6 (6) ◽  
pp. e609 ◽  
Author(s):  
Kristen R. Hollinger ◽  
Matthew D. Smith ◽  
Leslie A. Kirby ◽  
Eva Prchalova ◽  
Jesse Alt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
T Cell Activation ◽  
Cognitive Deficits ◽  
Cell Activation ◽  
Immune Cell ◽  
Disease Onset ◽  
Treatment Paradigm ◽  
The Impact

ObjectiveTo measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS.MethodsSplenic-derived T cells and bone marrow–derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test.ResultsJHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment.ConclusionsJHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS.

Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors

2008 ◽  
Vol 389 (5) ◽  
Author(s):  
Szilvia Benkő ◽  
Zoltán Magyarics ◽  
Attila Szabó ◽  
Éva Rajnavölgyi
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cell Activation ◽  
Membrane Receptors ◽  
Fine Tuning ◽  
World Health ◽  
Functional Link ◽  
Recognition Systems ◽  
Molecular Patterns

Abstract Preventive vaccination is the most successful approach against infectious diseases and has a great impact on world health. Vaccines operate through the activation of innate immunity that helps to stimulate antigen-specific T- and B-lymphocytes. These events are orchestrated by dendritic cells (DCs) that are able to sample foreign structures and concomitantly sense ‘danger signals’. Thus, DCs provide a functional link between innate and acquired immunity, and due to their regulatory potential are referred to as natural adjuvants. Human conventional and plasmacytoid DCs express different sets of well-characterized Toll-like membrane receptors (TLRs) that recognize a broad range of conserved molecular patterns of pathogens. The recently discovered cytosolic Nod-like receptors (NLRs) and RIG-like helicases (RLHs) also turned out to participate in pathogen recognition and modulation of immune responses through interacting signaling pathways. As a result of their collaboration, the TLR, NLR and RLH recognition systems induce the secretion of different combinations of cytokines that play a fundamental role in T-cell activation and instruction. Ligands of the innate recognition systems emerge as new adjuvants for vaccine design, whereas manipulation of the signaling pathways mediated by these receptors offers new avenues for fine tuning immune responses and optimizing immunotherapies.

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