scholarly journals Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis

2021 ◽  
Vol 22 (17) ◽  
pp. 9449
Author(s):  
Davide Ferrari ◽  
Fabio Casciano ◽  
Paola Secchiero ◽  
Eva Reali
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Purinergic Signaling ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Inflammasome Activation ◽  
Increased Risk

Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques’ formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes’ inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments.

scholarly journals NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 692
Author(s):  
Carrie-Anne Malinczak ◽  
Charles F. Schuler ◽  
Angela J. Duran ◽  
Andrew J. Rasky ◽  
Mohamed M. Mire ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Severe Disease ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Increased Risk ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

scholarly journals Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

2014 ◽  
Vol 211 (10) ◽  
pp. 2047-2059 ◽  
Author(s):  
Peter D. Kurktschiev ◽  
Bijan Raziorrouh ◽  
Winfried Schraut ◽  
Markus Backmund ◽  
Martin Wächtler ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Critical Role ◽  
Interferon Γ ◽  
Strongly Correlated

The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet–deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet+ CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.

scholarly journals Annexin A5 is essential for PKCθ translocation during T-cell activation

2020 ◽  
Vol 295 (41) ◽  
pp. 14214-14221
Author(s):  
Zhaoqing Hu ◽  
Lin Li ◽  
Banghui Zhu ◽  
Yi Huang ◽  
Xinran Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Annexin A5 ◽  
Activated T Cells ◽  
Calcium Dependent

T-cell activation is a critical part of the adaptive immune system, enabling responses to foreign cells and external stimulus. In this process, T-cell antigen receptor (TCR) activation stimulates translocation of the downstream kinase PKCθ to the membrane, leading to NF-κB activation and thus transcription of relevant genes. However, the details of how PKCθ is recruited to the membrane remain enigmatic. It is known that annexin A5 (ANXA5), a calcium-dependent membrane-binding protein, has been reported to mediate PKCδ activation by interaction with PKCδ, a homologue of PKCθ, which implicates a potential role of ANXA5 involved in PKCθ signaling. Here we demonstrate that ANXA5 does play a critical role in the recruitment of PKCθ to the membrane during T-cell activation. ANXA5 knockout in Jurkat T cells substantially inhibited the membrane translocation of PKCθ upon TCR engagement and blocked the recruitment of CARMA1-BCL10-MALT1 signalosome, which provides a platform for the catalytic activation of IKKs and subsequent activation of canonical NF-κB signaling in activated T cells. As a result, NF-κB activation was impaired in ANXA5-KO T cells. T-cell activation was also suppressed by ANAX5 knockdown in primary T cells. These results demonstrated a novel role of ANXA5 in PKC translocation and PKC signaling during T-cell activation.

Bidirectional Effects of Corticosterone on Splenic T-Cell Activation: Critical Role of Cell Density and Culture Time

2001 ◽  
Vol 73 (2) ◽  
pp. 139-148 ◽  
Author(s):  
G. Jan Wiegers ◽  
Ilona E.M. Stec ◽  
Wolfgang E.F. Klinkert ◽  
Astrid C.E. Linthorst ◽  
Johannes M.H.M. Reul
Keyword(s):  
T Cell ◽  
Cell Density ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Culture Time ◽  
Bidirectional Effects

scholarly journals Transcriptional Analysis-Based Alterations Affecting Neuritogenesis of the Peripheral Nervous System in Psoriasis

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 111
Author(s):  
Dóra Romhányi ◽  
Kornélia Szabó ◽  
Lajos Kemény ◽  
Endre Sebestyén ◽  
Gergely Groma
Keyword(s):  
Nervous System ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Nervous System Development ◽  
Axonal Guidance ◽  
Transcriptional Analysis ◽  
Psoriatic Skin ◽  
Depth Analysis

An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related process. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T-cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.

scholarly journals Association of Polymorphisms in T-Cell Activation Costimulatory/Inhibitory Signal Genes With Allograft Kidney Rejection Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose Luis Santiago ◽  
Luis Sánchez-Pérez ◽  
Isabel Pérez-Flores ◽  
Maria Angeles Moreno de la Higuera ◽  
Natividad Calvo Romero ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Induction Therapy ◽  
Cell Activation ◽  
Critical Role ◽  
Cell Immune Response ◽  
Nucleotide Polymorphisms ◽  
Antibody Mediated Rejection ◽  
Allograft Kidney

The genes CD28, CD86 and CTLA-4 conform the costimulatory (CD28-CD86) or inhibitory (CTLA-4-CD86) signal in T-cell activation. T-cell immune response has a critical role in allograft rejection, and single nucleotide polymorphisms (SNPs) located in these genes have been widely analyzed with controversial results. We analyzed a group of SNPs located in the three genes: CD28: rs3116496; CD86: rs1129055; and CTLA-4: rs231775 and rs3087243 in a cohort of 632 consecutively recruited kidney transplanted subjects. All polymorphisms were genotyped by TaqMan chemistry and the diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. The analyses showed a statistically significant protective effect to T cell-mediated rejection (TCMR) in carriers of the CTLA-4 rs3087243*G allele, especially in patients with TCMR Banff ≥2 in the overall cohort and in patients without thymoglobulin induction therapy. Both associations were corroborated as independent factors in the multivariate analysis. Interestingly, associations with rejection were not found for any SNP in patients with thymoglobulin induction therapy. As expected, considering the major role of these genes in T-cell activation, no effect was observed for antibody-mediated rejection (ABMR). In conclusion, the SNP rs3087243 located in the CTLA-4 gene may be considered a useful independent biomarker for TCMR risk especially for severe TCMR in patients who did no received thymoglobulin induction therapy.

scholarly journals Targeting Myeloid-Derived Suppressor Cells Is a Novel Strategy for Anti-Psoriasis Therapy

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Chao Chen ◽  
Lirong Tan ◽  
Wu Zhu ◽  
Li Lei ◽  
Yehong Kuang ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Myeloid Derived Suppressor Cells ◽  
Th17 Cell Differentiation ◽  
Cell Accumulation ◽  
Psoriasis Therapy ◽  
Novel Strategy

Psoriasis is a common immune-mediated, chronic inflammatory genetic-related disease that affects patients’ quality of life. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of progenitor and immature myeloid cells which are expanded in psoriatic skin lesions and peripheral blood. However, the role of MDSCs in the pathogenesis of psoriasis remains unclear. Here, we confirmed that the accumulation of human MDSCs is remarkably increased in skin lesions of psoriasis patients by flow cytometry. Depleting MDSCs by Gemcitabine significantly suppresses IMQ-induced psoriatic inflammation and epidermal thickening as well as Th17 and Treg cell accumulation. Moreover, through the RNA-Seq technique, we validated some differentially expressed genes on CD4+ T-cells of IMQ-induced-MDSC-depleted mice such as IL-21 and Timd2, which are involved in Th17-cell differentiation or T-cell activation. Interestingly, neutralizing IL-21R by antibody reduces IMQ-induced epidermal thickening through downregulating the infiltration of MDSCs and Th17 cells. Our data suggest that targeting myeloid-derived suppressor cells is a novel strategy for antipsoriasis therapy. IL-21 may be a potential therapeutic target in psoriasis.

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