Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages

2007 ◽  
Vol 214 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Mark A. Birrell ◽  
Sissie Wong ◽  
Matthew C. Catley ◽  
Maria G. Belvisi
Keyword(s):  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Tobacco Smoke ◽  
Innate Immune ◽  
Lung Macrophages

scholarly journals Mitochondrial UPR negatively regulates wounding-induced innate immune response in C. elegans epidermis

2021 ◽  
Author(s):  
Jianzhi Zhao ◽  
Hongying Fu ◽  
Hengda Zhou ◽  
Xuecong Ren ◽  
Yuanyuan Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Tissue Damage ◽  
P38 Map Kinase ◽  
Innate Immune ◽  
Loss Of Function ◽  
C Elegans ◽  
Unfolded Protein ◽  
Protein Response

Tissue damage elicits a rapid innate immune response that is essential for efficient wound healing and survival of metazoans. It is well known that p38 MAPK kinase, TGF-β, and hemidesmosome signaling pathways have been involved in wounding-induced innate immunity in C. elegans. Here, we find that loss of function of ATFS-1 increased innate immune response while an elevated level of mitochondrial unfolded protein response (mitoUPR) inhibits the innate immune response upon epidermal wounding. Epidermal wounding triggers the nucleus export of ATFS-1 and inhibits themitoUPR in C. elegans epidermis. Moreover, genetic analysis suggests that ATFS-1 functions upstream of the p38 MAP kinase, TGF-β, and DAF-16 signaling pathways in regulating AMPs induction. Thus, our results suggest that the mitoUPR function as an intracellular signal required to fine-tune innate immune response after tissue damage.

scholarly journals Relative Contributions of the cGAS-STING and TLR3 Signaling Pathways to Attenuation of Herpes Simplex Virus 1 Replication

2020 ◽  
Vol 94 (6) ◽  
Author(s):  
Muhammad Bilal Latif ◽  
Rameez Raja ◽  
Patricia M. Kessler ◽  
Ganes C. Sen
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Innate Immune Response ◽  
Human Cell ◽  
Innate Immune ◽  
Human Cell Lines ◽  
Herpes Simplex Virus 1 ◽  
Hsv 1

ABSTRACT The innate immune response is crucial for defense against viral infections. Cells recognize virus infection through pattern recognition receptors and induce type I interferons as well as proinflammatory cytokines to orchestrate an innate immune response. Herpes simplex virus 1 (HSV-1) triggers both the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) and Toll-like receptor 3 (TLR3) pathways. It is well known that TLR3 uses the adaptor protein Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing beta interferon (TRIF) for signaling, but we recently reported that STING signaling also requires TRIF. Because STING directly binds to TRIF, we identified the STING-interacting domain of TRIF and generated STING-noninteracting mutants of human and mouse TRIFs. The mutant TRIFs were unable to support STING signaling, although they were fully functional in the TLR3 pathway. These mutants were used to assess the relative contributions of the TLR3 and STING pathways to the attenuation of HSV-1 replication in mouse and human cell lines. For this purpose, the mouse L929 and NB41A3 cell lines and the human HT1080 and HeLa-M cell lines, in which both the TLR3 and the STING pathways are operational, were used. The TRIF gene was disrupted in these lines by CRISPR/Cas9, before reconstituting them with mutant and wild-type TRIF expression vectors. Infection of the reconstituted cells with HSV-1 revealed that both the cGAS-STING and the TLR3 signaling pathways are required for the attenuation of virus replication, but their relative contributions in attenuating HSV-1 replication were found to be different in mouse versus human cell lines. Thus, our study suggests that the relative contributions of the cGAS-STING and the TLR3 pathways in the attenuation of viral infection may be species specific. IMPORTANCE The magnitude of fatal infections caused by all different viruses in human and animal populations justifies a better understanding of the host innate immune response process that attenuates virus replication. In particular, the relative contributions of different signaling pathways which are responsible for the generation of the innate immune response are still largely unknown. In this study, we used STING-noninteracting TRIF mutants to decipher the relative contributions of the TLR3 and cGAS-STING signaling pathways to the attenuation of HSV-1 infection. We show that the relative contributions of the two pathways to the attenuation of viral infection are different in mouse versus human cell lines. Together, our results provide new insights into the relative contributions of two different signaling pathways in the attenuation of viral infection and may lead to the development of new antiviral strategies aimed at blocking viral infection at very early stages.

scholarly journals RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model

2018 ◽  
Vol 92 (13) ◽  
pp. e02246-17 ◽  
Author(s):  
Shintaro Yamada ◽  
Masayuki Shimojima ◽  
Ryo Narita ◽  
Yuta Tsukamoto ◽  
Hiroki Kato ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Immune Response ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Cytokines And Chemokines ◽  
Severe Fever

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family Bunyaviridae, SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1−/−) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production in vivo and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1−/− MyD88−/− mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease. IMPORTANCE SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.

scholarly journals Skin Commensals Amplify the Innate Immune Response to Pathogens by Activation of Distinct Signaling Pathways

2011 ◽  
Vol 131 (2) ◽  
pp. 382-390 ◽  
Author(s):  
Ines Wanke ◽  
Heiko Steffen ◽  
Christina Christ ◽  
Bernhard Krismer ◽  
Friedrich Götz ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Skin Commensals

scholarly journals Requirement of Split ends for Epigenetic Regulation of Notch Signal-Dependent Genes during Infection-Induced Hemocyte Differentiation

2009 ◽  
Vol 29 (6) ◽  
pp. 1515-1525 ◽  
Author(s):  
Li Hua Jin ◽  
Jung Kyoon Choi ◽  
Byungil Kim ◽  
Hwan Sung Cho ◽  
Jihyun Kim ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Neuronal Development ◽  
Chromatin Modification ◽  
Notch Pathway ◽  
Innate Immune ◽  
Mutant Form ◽  
Dependent Manner ◽  
Split Ends

ABSTRACT Drosophila producing a mutant form of the putative transcription coregulator, Split ends (Spen), originally identified in the analysis of neuronal development, display diverse immune defects. In order to understand the role of Spen in the innate immune response, we analyzed the transcriptional defects associated with spen mutant hemocytes and their relationship to the Notch signaling pathways. Spen is regulated by the Notch pathway in the lymph glands and is required for Notch-dependent activation of a large number of genes involved in energy metabolism and differentiation. Analysis of the epigenetic marks associated with Spen-dependent genes indicates that Spen performs its function as a coactivator by regulating chromatin modification. Intriguingly, expression of the Spen-dependent genes was transiently downregulated in a Notch-dependent manner by the Dif activated upon recognition of pathogen-associated molecules, demonstrating the existence of cross talk between hematopoietic regulation and the innate immune response. Our observations reveal a novel connection between the Notch and Toll/IMD signaling pathways and demonstrate a coactivating role for Spen in activating Notch-dependent genes in differentiating cells.

scholarly journals Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Daniel L. Bourque ◽  
Taufiqur Rahman Bhuiyan ◽  
Diane P. Genereux ◽  
Rasheduzzaman Rashu ◽  
Crystal N. Ellis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Content Type ◽  
Upstream Regulators

ABSTRACTTo better understand the innate immune response toVibrio choleraeinfection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor geneTLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signalingin vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases inDUOX2andTLR8expression were also modeledin vitrowhen Caco-2 or THP-1 cells, respectively, were stimulated with liveV. choleraebut not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response toV. choleraeextend our understanding of the mucosal immune signaling pathways and effectors activatedin vivofollowing cholera.

scholarly journals Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 292 ◽  
Author(s):  
Irene Lo Cigno ◽  
Federica Calati ◽  
Silvia Albertini ◽  
Marisa Gariglio
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Human Papillomavirus ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Immune Escape ◽  
Innate Immune ◽  
Transformed Cells ◽  
Type I ◽  
E6 And E7

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated.

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