scholarly journals β-Defensin Strengthens Antimicrobial Peritoneal Mast Cell Response

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Justyna Agier ◽  
Ewa Brzezińska-Błaszczyk ◽  
Sylwia Różalska ◽  
Magdalena Wiktorska ◽  
Sebastian Wawrocki ◽  
...  
Keyword(s):  
Immune Response ◽  
Host Defense ◽  
Peritoneal Mast Cell ◽  
Pathogen Defense ◽  
Migratory Response ◽  
Mrna And Protein Expression ◽  
Molecular Patterns ◽  
Defense Molecules ◽  
Ongoing Infection ◽  
Inducible Gene

Mast cells (MCs) are engaged in the processes of host defense, primarily via the presence of receptors responsible for the detection of pathogen-associated molecular patterns (PAMPs). Since BDs are exclusively host defense molecules, and MCs can elicit the antimicrobial response, this study is aimed at determining whether BDs might be involved in MC pathogen defense. We found that defensin BD-2 significantly augments the mRNA and protein expression of Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptor (RLR) essential for the detection of viral molecules, i.e., TLR3, TLR7, TLR9, and RIG-I in mature tissue rat peritoneal MCs (PMCs). We established that BD-2 might stimulate PMCs to release proinflammatory and immunoregulatory mediators and to induce a migratory response. Presented data on IgE-coated PMC upon BD-2 treatment suggest that in the case of allergies, there is an enhanced MC immune response and cell influx to the site of the ongoing infection. In conclusion, our data highlight that BD-2 might strongly influence MC features and activity, mainly by strengthening their role in the inflammatory mechanisms and controlling the activity of cells participating in antimicrobial processes.

scholarly journals Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

2020 ◽  
Vol 21 (21) ◽  
pp. 8090
Author(s):  
Roya Rasaei ◽  
Neha Sarodaya ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna ◽  
Seok-Ho Hong
Keyword(s):  
Immune Response ◽  
Small Molecule ◽  
Host Defense ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Genetic Material ◽  
Immune Signaling ◽  
Ubiquitin System ◽  
Autoimmune And Inflammatory Diseases ◽  
Molecular Patterns

Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.

TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

2021 ◽  
Author(s):  
Chen Chen ◽  
Chengguang Zhang ◽  
Haoqi Li ◽  
Zongmei Wang ◽  
Yueming Yuan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Rabies Virus ◽  
Humoral Immunity ◽  
Humoral Immune Response ◽  
Critical Role ◽  
Wild Type ◽  
Humoral Immune ◽  
Specific Igg ◽  
Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

scholarly journals Megakaryocyte derived immune-stimulating cells regulate host-defense immunity against bacterial pathogens

2021 ◽  
Author(s):  
Jin Wang ◽  
Jiayi Xie ◽  
Xue Han ◽  
Daosong Wang ◽  
Minqi Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Bacterial Infection ◽  
Host Defense ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hematopoietic Stem ◽  
Bacterial Response ◽  
Stem Cell Quiescence ◽  
Express Cell

Megakaryocytes (MKs) continuously produce platelets in bone marrow to support hemostasis. However, MKs also play roles beyond thrombopoiesis as they regulate hematopoietic stem cell quiescence and erythropoiesis, which suggests the functional heterogeneity of MKs. Here, using single-cell sequencing we identified an MK-derived immune-stimulating cell (MDIC) population, which plays an important role in host-protective response against bacteria. In contrast to platelet-generating MKs, MDICs highly express cell migration, immune-modulatory, and response genes. Upon Listeria (L.) monocytogenes infection, MDICs egress to circulation and infiltrate into the spleen, liver and lung. MDICs interact with myeloid cells to promote their migration and tissue infiltration. More importantly, MDICs stimulate phagocytosis of macrophages and neutrophils by producing TNFα and IL-6 and facilitating antigen-specific T cell activation via IL-6 to enhance anti-bacterial response. Ablation of MKs reduced innate immune response and compromised T cell activation in spleen and liver, impairs the anti-bacterial effects in mice under L. monocytogenes challenge. Finally, infection-induced emergency megakaryopoiesis efficiently stimulated MDICs generation upon bacterial infection. Overall, we identify MDICs as a novel MK subpopulation, which regulates host-defense immune response against bacterial infection.

scholarly journals Peptide Aggregation Induced Immunogenic Rupture (PAIIR)

2021 ◽  
Author(s):  
Gokhan Gunay ◽  
Seren Hamsici ◽  
Handan Acar ◽  
Mark L. Lang ◽  
Gillian A. Lang ◽  
...  
Keyword(s):  
Immune Response ◽  
Membrane Damage ◽  
Cell Types ◽  
Peptide Aggregation ◽  
Vaccine Adjuvants ◽  
Humoral And Cellular Immunity ◽  
Influenza Hemagglutinin ◽  
Series Of Experiments ◽  
Molecular Patterns

Under the influence of stress and membrane damage, cells undergo immunogenic cell death (ICD), which involves the release of damage associated molecular patterns (DAMPs), natural adjuvants for enhancing an immune response. In the presence of an antigen, released DAMPs can determine the type and magnitude of the immune response, and therefore the longevity and efficacy of an antigen-specific immunity. In the last decade, the immune response effect of ICD has been shown, yet there is no tool that can induce controlled ICD with predictable results, regardless of the cell type. We designed a peptide-based tool, called [II], for controlled damage to cell membrane to induce ICD and DAMPs release. Herein we describe a series of experiments that determine that the mechanism of action of [II] includes a caspase-dependent ICD and subsequent release of immune stimulating DAMPs, on various cell types. Moreover, we tested the hypothesis that controlled DAMP release via [II] in vivo was associated with enhancement of antigen-specific adaptive immunity with influenza hemagglutinin (HA) subunit vaccine. HA and [II] showed significantly higher HA specific IgG1 and IgG2a antibodies, compared to HA-only immunized mice, while the peptide itself did not elicit antibodies. In this paper, we demonstrate the first peptide-aggregation induced immunogenic rupture (PAIIR) approach as vaccine adjuvants for increasing both humoral and cellular immunity. In consideration of its ability to enhance IgG2a responses that are associated with heterosubtypic influenza virus protection, PAIIR is a promising adjuvant to promote universal protection upon influenza HA vaccination.

scholarly journals Differential Requirements for Mediator Complex Subunits in Drosophila melanogaster Host Defense Against Fungal and Bacterial Pathogens

2021 ◽  
Vol 11 ◽  
Author(s):  
Chuqin Huang ◽  
Rui Xu ◽  
Samuel Liégeois ◽  
Di Chen ◽  
Zi Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Host Defense ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Transcriptional Response ◽  
Erwinia Carotovora ◽  
Mediator Complex ◽  
Toll Pathway ◽  
Metarhizium Robertsii ◽  
Immune Factor

The humoral immune response to bacterial or fungal infections in Drosophila relies largely on a transcriptional response mediated by the Toll and Immune deficiency NF-κB pathways. Antimicrobial peptides are potent effectors of these pathways and allow the organism to attack invading pathogens. Dorsal-related Immune Factor (DIF), a transcription factor regulated by the Toll pathway, is required in the host defense against fungal and some Gram-positive bacterial infections. The Mediator complex is involved in the initiation of transcription of most RNA polymerase B (PolB)-dependent genes by forming a functional bridge between transcription factors bound to enhancer regions and the gene promoter region and then recruiting the PolB pre-initiation complex. Mediator is formed by several modules that each comprises several subunits. The Med17 subunit of the head module of Mediator has been shown to be required for the expression of Drosomycin, which encodes a potent antifungal peptide, by binding to DIF. Thus, Mediator is expected to mediate the host defense against pathogens controlled by the Toll pathway-dependent innate immune response. Here, we first focus on the Med31 subunit of the middle module of Mediator and find that it is required in host defense against Aspergillus fumigatus, Enterococcus faecalis, and injected but not topically-applied Metarhizium robertsii. Thus, host defense against M. robertsii requires Dif but not necessarily Med31 in the two distinct infection models. The induction of some Toll-pathway-dependent genes is decreased after a challenge of Med31 RNAi-silenced flies with either A. fumigatus or E. faecalis, while these flies exhibit normal phagocytosis and melanization. We have further tested most Mediator subunits using RNAi by monitoring their survival after challenges to several other microbial infections known to be fought off through DIF. We report that the host defense against specific pathogens involves a distinct set of Mediator subunits with only one subunit for C. glabrata or Erwinia carotovora carotovora, at least one for M. robertsii or a somewhat extended repertoire for A. fumigatus (at least eight subunits) and E. faecalis (eight subunits), with two subunits, Med6 and Med11 being required only against A. fumigatus. Med31 but not Med17 is required in fighting off injected M. robertsii conidia. Thus, the involvement of Mediator in Drosophila innate immunity is more complex than expected.

scholarly journals Salmonella’s Sensor for Host Defense Molecules

Cell ◽  
2005 ◽  
Vol 122 (3) ◽  
pp. 320-322 ◽  
Author(s):  
Robert E.W. Hancock ◽  
Joseph B. McPhee
Keyword(s):  
Host Defense ◽  
Defense Molecules

Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 660-669 ◽  
Author(s):  
Maria Teresa Sabrina Bertilaccio ◽  
Giorgia Simonetti ◽  
Antonis Dagklis ◽  
Martina Rocchi ◽  
Tania Veliz Rodriguez ◽  
...  
Keyword(s):  
Immune Response ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Adaptive Immune Response ◽  
Lymphocytic Leukemia ◽  
Fine Tuning ◽  
Terminal Phase ◽  
Lymphoid Malignancies ◽  
History Of ◽  
Molecular Patterns

Abstract Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R–like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed Eμ-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression.

2. First responders: the innate immune response

2017 ◽  
pp. 17-29
Author(s):  
Paul Klenerman
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Acute Phase Response ◽  
First Responders ◽  
Fundamental Question ◽  
Innate Immune ◽  
Rapid Action ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

How does the immune system know when to respond? ‘First responders: the innate immune response’ considers this fundamental question that is central to understanding both normal (e.g. to infections) and abnormal (e.g. in auto-immune diseases) responses; and designing vaccines and new therapies in cancer and infectious diseases. It looks at how ‘danger’ is sensed by the immune system through pathogen-associated molecular patterns and damage-associated molecular patterns. Having been alerted, it is important that rapid action is taken to limit the spread of a pathogen. A number of responses can be initiated immediately, forming a critical part of our innate immunity, which are followed by the acute phase response.

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