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Cell Communication and Signaling : CCS Oct 2023Pyroptosis is crucial for controlling various immune cells. However, the role of allergen-induced CD11c + dendritic cell (DC) pyroptosis in allergic rhinitis (AR)...
BACKGROUND
Pyroptosis is crucial for controlling various immune cells. However, the role of allergen-induced CD11c + dendritic cell (DC) pyroptosis in allergic rhinitis (AR) remains unclear.
METHODS
Mice were grouped into the control group, AR group and necrosulfonamide-treated AR group (AR + NSA group). The allergic symptom scores, OVA-sIgE titres, serum IL-1β/IL-18 levels, histopathological characteristics and T-helper cell-related cytokines were evaluated. CD11c/GSDMD-N-positive cells were examined by immunofluorescence analysis. Murine CD11c + bone marrow-derived DCs (BMDCs) were induced in vitro, stimulated with OVA/HDM, treated with necrosulfonamide (NSA), and further cocultured with lymphocytes to assess BMDC function. An adoptive transfer murine model was used to study the role of BMDC pyroptosis in allergic rhinitis.
RESULTS
Inhibiting GSDMD-N-mediated pyroptosis markedly protected against Th1/Th2/Th17 imbalance and alleviated inflammatory responses in the AR model. GSDMD-N was mainly coexpressed with CD11c (a DC marker) in AR mice. In vitro, OVA/HDM stimulation increased pyroptotic morphological abnormalities and increased the expression of pyroptosis-related proteins in a dose-dependent manner; moreover, inhibiting pyroptosis significantly decreased pyroptotic morphology and NLRP3, C-Caspase1 and GSDMD-N expression. In addition, OVA-induced BMDC pyroptosis affected CD4 + T-cell differentiation and related cytokine levels, leading to Th1/Th2/Th17 cell imbalance. However, the Th1/Th2/Th17 cell immune imbalance was significantly reversed by NSA. Adoptive transfer of OVA-loaded BMDCs promoted allergic inflammation, while the administration of NSA to OVA-loaded BMDCs significantly reduced AR inflammation.
CONCLUSION
Allergen-induced dendritic cell pyroptosis promotes the development of allergic rhinitis through GSDMD-N-mediated pyroptosis, which provides a clue to allergic disease interventions. Video Abstract.
Topics: Animals; Mice; Allergens; Pyroptosis; Rhinitis, Allergic; Cytokines; Inflammation; Dendritic Cells; Mice, Inbred BALB C
PubMed: 37817225
DOI: 10.1186/s12964-023-01309-8 -
JCI Insight Jul 2023Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic...
Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic function. To determine the function of TSLP in barrier sites, we investigated the impact of endogenous TSLP signaling on the homeostatic expansion of CD4+ T cells in adult mice. Surprisingly, incoming CD4+ T cells induced lethal colitis in adult Rag1-knockout animals that lacked the TSLP receptor (Rag1KOTslprKO). Endogenous TSLP signaling was required for reduced CD4+ T cell proliferation, Treg differentiation, and homeostatic cytokine production. CD4+ T cell expansion in Rag1KOTslprKO mice was dependent on the gut microbiome. The lethal colitis was rescued by parabiosis between Rag1KOTslprKO and Rag1KO animals and wild-type dendritic cells (DCs) suppressed CD4+ T cell-induced colitis in Rag1KOTslprKO mice. A compromised T cell tolerance was noted in TslprKO adult colon, which was exacerbated by anti-PD-1 and anti-CTLA-4 therapy. These results reveal a critical peripheral tolerance axis between TSLP and DCs in the colon that blocks CD4+ T cell activation against the commensal gut microbiome.
Topics: Animals; Mice; CD4-Positive T-Lymphocytes; Cell Differentiation; Colitis; Cytokines; Dendritic Cells; Gastrointestinal Microbiome; T-Lymphocytes, Regulatory; Thymic Stromal Lymphopoietin
PubMed: 37427591
DOI: 10.1172/jci.insight.160690 -
Frontiers in Immunology 2023Dendritic cells (DCs), central participants in the allergic immune response, can capture and present allergens leading to allergic inflammation in the immunopathogenesis... (Review)
Review
Dendritic cells (DCs), central participants in the allergic immune response, can capture and present allergens leading to allergic inflammation in the immunopathogenesis of allergic rhinitis (AR). In addition to initiating antigen-specific immune responses, DCs induce tolerance and modulate immune homeostasis. As a special type of DCs, tolerogenic DCs (tolDCs) achieve immune tolerance mainly by suppressing effector T cell responses and inducing regulatory T cells (Tregs). TolDCs suppress allergic inflammation by modulating immune tolerance, thereby reducing symptoms of AR. Activation of the TLR4/IRAK4/NF-κB signaling pathway contributes to the release of inflammatory cytokines, and inhibitors of this signaling pathway induce the production of tolDCs to alleviate allergic inflammatory responses. This review focuses on the relationship between tolDCs and TLR4/IRAK4/NF-κB signaling pathway with AR.
Topics: Humans; NF-kappa B; Toll-Like Receptor 4; Interleukin-1 Receptor-Associated Kinases; Rhinitis, Allergic; Signal Transduction; Inflammation; Dendritic Cells
PubMed: 37915574
DOI: 10.3389/fimmu.2023.1276512 -
European Journal of Immunology Dec 2023This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis...
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)-presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
Topics: Humans; Proteomics; Dendritic Cells; Flow Cytometry; Gene Expression Profiling; Cross-Priming
PubMed: 36563126
DOI: 10.1002/eji.202249925 -
Frontiers in Immunology 2023cDC2s occur abundantly in peripheral tissues and arise from circulating blood cDC2s. However, the factors governing cDC2 differentiation in tissues, especially under...
cDC2s occur abundantly in peripheral tissues and arise from circulating blood cDC2s. However, the factors governing cDC2 differentiation in tissues, especially under inflammatory conditions, remained poorly defined. We here found that psoriatic cDC2s express the efferocytosis receptor Axl and exhibit a bone morphogenetic protein (BMP) and p38MAPK signaling signature. BMP7, strongly expressed within the lesional psoriatic epidermis, cooperates with canonical TGF-β1 signaling for inducing AxlcDC2s from blood cDC2s . Moreover, downstream induced p38MAPK promotes AxlcDC2s at the expense of AxlCD207 Langerhans cell differentiation from blood cDC2s. BMP7 supplementation allowed to model cDC2 generation and their further differentiation into LCs from CD34 hematopoietic progenitor cells in defined serum-free medium. Additionally, p38MAPK promoted the generation of another cDC2 subset lacking Axl but expressing the non-classical NFkB transcription factor RelB . Such RelBcDC2s occurred predominantly at dermal sites in the inflamed skin. Finally, we found that cDC2s can be induced to acquire high levels of the monocyte lineage identity factor kruppel-like-factor-4 (KLF4) along with monocyte-derived DC and macrophage phenotypic characteristics In conclusion, inflammatory and psoriatic epidermal signals instruct blood cDC2s to acquire phenotypic characteristics of several tissue-resident cell subsets.
Topics: Humans; Monocytes; Dendritic Cells; Cell Differentiation; Skin; Epidermis
PubMed: 37539048
DOI: 10.3389/fimmu.2023.1216352 -
Cell Reports Aug 2023Conventional dendritic cells (cDCs) are found in most tissues and play a key role in initiation of immunity. cDCs require constant replenishment from progenitors called...
Conventional dendritic cells (cDCs) are found in most tissues and play a key role in initiation of immunity. cDCs require constant replenishment from progenitors called pre-cDCs that develop in the bone marrow (BM) and enter the blood circulation to seed all tissues. This process can be markedly accelerated in response to inflammation (emergency cDCpoiesis). Here, we identify two populations of BM pre-cDC marked by differential expression of CXCR4. We show that CXCR4 cells constitute the migratory pool of BM pre-cDCs, which exits the BM and can be rapidly mobilized during challenge. We further show that exit of CXCR4 pre-cDCs from BM at steady state is partially dependent on CCR2 and that CCR2 upregulation in response to type I IFN receptor signaling markedly increases efflux during infection with influenza A virus. Our results highlight a fine balance between retention and efflux chemokine cues that regulates steady-state and emergency cDCpoiesis.
Topics: Bone Marrow; Bone Marrow Cells; Dendritic Cells; Inflammation; Receptors, CCR2; Receptors, CXCR4; Signal Transduction; Animals
PubMed: 37523265
DOI: 10.1016/j.celrep.2023.112881 -
Cell Reports. Medicine Dec 2023FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluate cancer growth in mice with low, normal, or high levels...
FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluate cancer growth in mice with low, normal, or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma. In low cDC context, tumors are restrained by the adaptive immune system through influx of effector T cells and depletion of Tregs and NK cells. High cDC numbers favor the innate anti-tumor response, with massive recruitment of activated NK cells, despite high Treg infiltration. Anti CTLA-4 but not anti PD-1 therapy synergizes with FLT3-L therapy in the cDC but not in the cDC context. A combination of cDC boost and Treg depletion dramatically improves survival of tumor-bearing mice. Transcriptomic data confirm the paradoxical effect of cDC levels on survival in several human tumor types. cDC-Treg state in such patients predicts best survival. Modulating cDC numbers via FLT3 signaling may have therapeutic potential in human cancer.
Topics: Humans; Mice; Animals; T-Lymphocytes, Regulatory; Neoplasms; Killer Cells, Natural; Dendritic Cells; Homeostasis
PubMed: 38118422
DOI: 10.1016/j.xcrm.2023.101256 -
Frontiers in Immunology 2024Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC... (Review)
Review
Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.
Topics: Humans; Dendritic Cells; Neoplasms; Tumor Microenvironment; Immunotherapy; Animals
PubMed: 38903502
DOI: 10.3389/fimmu.2024.1393451 -
International Journal of Molecular... Dec 2023Allergic rhinitis (AR) is a common pathological condition in otorhinolaryngology. Its prevalence has been increasing worldwide and is becoming a major burden to the... (Review)
Review
Allergic rhinitis (AR) is a common pathological condition in otorhinolaryngology. Its prevalence has been increasing worldwide and is becoming a major burden to the world population. Dendritic cells (DCs) are typically activated and matured after capturing, phagocytosing, and processing allergens during the immunopathogenesis of AR. In addition, the process of DC activation and maturation is accompanied by the production of exosomes, which are cell‑derived extracellular vesicles (EVs) that can carry proteins, lipids, nucleic acids, and other cargoes involved in intercellular communication and material transfer. In particular, DC‑derived exosomes (Dex) can participate in allergic immune responses, where the biological substances carried by them can have potentially important implications for both the pathogenesis and treatment of AR. Dex can also be exploited to carry anti‑allergy agents to effectively treat AR. This provides a novel method to explore the pathogenesis of and treatment strategies for AR further. Therefore, the present review focuses on the origin, composition, function, and biological characteristics of DCs, exosomes, and Dex, in addition to the possible relationship between Dex and AR.
Topics: Humans; Exosomes; Rhinitis, Allergic; Allergens; Extracellular Vesicles; Dendritic Cells
PubMed: 37888754
DOI: 10.3892/ijmm.2023.5320 -
Advanced Science (Weinheim,... Nov 2023Spleen and lymphoid organs are important targets for messenger RNA (mRNA) delivery in various applications. Current nanoparticle delivery methods rely on drainage to...
Spleen and lymphoid organs are important targets for messenger RNA (mRNA) delivery in various applications. Current nanoparticle delivery methods rely on drainage to lymph nodes from intramuscular or subcutaneous injections. In difficult-to-transfect antigen-presenting cells (APCs), such as dendritic cells (DCs), effective mRNA transfection remains a significant challenge. In this study, a lymphatic targeting carrier using DC membranes is developed, that efficiently migrated to lymphoid organs, such as the spleen and lymph nodes. The nanoparticles contained an ionizable lipid (YK009), which ensured a high encapsulation efficacy of mRNA and assisted mRNA with endosomal escape after cellular uptake. Dendritic cell-mimicking nanoparticles (DCMNPs) showed efficient protein expression in both the spleen and lymph nodes after intramuscular injections. Moreover, in immunized mice, DCMNP vaccination elicited Spike-specific IgG antibodies, neutralizing antibodies, and Th1-biased SARS-CoV-2-specific cellular immunity. This work presents a powerful vaccine formula using DCMNPs, which represents a promising vaccine candidate for further research and development.
Topics: Mice; Animals; Dendritic Cells; RNA, Messenger; Nanoparticles; Immunity, Cellular; Vaccines
PubMed: 37867227
DOI: 10.1002/advs.202302423