scholarly journals The colonic macrophage transcription factor RBP-J orchestrates intestinal immunity against bacterial pathogens

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Lan Kang ◽  
Xiang Zhang ◽  
Liangliang Ji ◽  
Tiantian Kou ◽  
Sinead M. Smith ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Late Phase ◽  
Intestinal Immunity ◽  
Adaptive Immune Responses ◽  
Cell Lineages ◽  
Adaptive Immune ◽  
Intestinal Macrophage ◽  
Pathogen Clearance

Macrophages play pleiotropic roles in maintaining the balance between immune tolerance and inflammatory responses in the gut. Here, we identified transcription factor RBP-J as a crucial regulator of colonic macrophage–mediated immune responses against the enteric pathogen Citrobacter rodentium. In the immune response phase, RBP-J promoted pathogen clearance by enhancing intestinal macrophage-elicited Th17 cell immune responses, which was achieved by maintenance of C/EBPβ-dependent IL-6 production by overcoming miRNA-17∼92–mediated suppressive effects. RBP-J deficiency–associated phenotypes could be genetically corrected by further deleting miRNA-17∼92 in macrophages. In the late phase, noneradicated pathogens in RBP-J KO mice recruited abundant IL-1β–expressing CD64+Ly6C+ colonic macrophages and thereby promoted persistence of ILC3-derived IL-22 to compensate for the impaired innate and adaptive immune responses, leading to ultimate clearance of pathogens. These results demonstrated that colonic macrophage–intrinsic RBP-J dynamically orchestrates intestinal immunity against pathogen infections by interfacing with key immune cells of T and innate lymphoid cell lineages.

scholarly journals Dual-Wavelength Photosensitive Nano-in-Micro Scaffold Regulates Innate and Adaptive Immune Responses for Osteogenesis

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Qin Zhao ◽  
Miusi Shi ◽  
Chengcheng Yin ◽  
Zifan Zhao ◽  
Jinglun Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
T Cell Response ◽  
Dual Wavelength ◽  
M2 Macrophage ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

AbstractThe immune response of a biomaterial determines its osteoinductive effect. Although the mechanisms by which some immune cells promote regeneration have been revealed, the biomaterial-induced immune response is a dynamic process involving multiple cells. Currently, it is challenging to accurately regulate the innate and adaptive immune responses to promote osteoinduction in biomaterials. Herein, we investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of biphasic calcium phosphate (BCP) scaffolds. We found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis. Accordingly, a dual-targeting nano-in-micro scaffold (BCP loaded with gold nanocage, BCP-GNC) was designed to regulate the immune responses of macrophages and DCs. Through a dual-wavelength photosensitive switch, BCP-GNC releases interleukin-4 in the early stage of osteoinduction to target M2 macrophages and then releases dexamethasone in the later stage to target immature DCs, creating a desirable inflammatory environment for osteogenesis. This study demonstrates that biomaterials developed to have specific regulatory capacities for immune cells can be used to control the early inflammatory responses of implanted materials and induce osteogenesis.

scholarly journals Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251885
Author(s):  
Lauryn Samelko ◽  
Marco Caicedo ◽  
Kyron McAllister ◽  
Joshua Jacobs ◽  
Nadim James Hallab
Keyword(s):  
Immune Responses ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Delayed Type Hypersensitivity ◽  
Adaptive Immune Responses ◽  
Male And Female ◽  
Female Mice ◽  
Adaptive Immune ◽  
Caspase 1 ◽  
Deficient Mice

It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL/6 vs. Caspase-1 deficient mice as well as young (12–16 weeks old) vs. aged (18–24 months old) female and male C57BL/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.

scholarly journals Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Young-Su Yi ◽  
Young-Jin Son ◽  
Chongsuk Ryou ◽  
Gi-Ho Sung ◽  
Jong-Hoon Kim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Adaptive Immune Responses ◽  
Functional Roles ◽  
Pathogen Invasion ◽  
Adaptive Immune ◽  
Biological Responses

Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

scholarly journals Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

2018 ◽  
Vol 215 (11) ◽  
pp. 2901-2918 ◽  
Author(s):  
Maria Buxadé ◽  
Hector Huerga Encabo ◽  
Marta Riera-Borrull ◽  
Lucía Quintana-Gallardo ◽  
Pilar López-Cotarelo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Cell Type ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Cell Type Specific ◽  
Antigen Presenting ◽  
Mhcii Expression

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type–specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

scholarly journals Leptin’s and antigen-presenting cells’ functions in periodontitis – an overview / Leptin e as funções das células que apresentam antigénios na periodontite - uma visão geral

2021 ◽  
Vol 4 (2) ◽  
pp. 8011-8019
Author(s):  
Giovanna Ganem Favero ◽  
Isabela Lopes Martin ◽  
Fernanda Pereira da Silva Albino ◽  
Carlos Eduardo Fontana ◽  
Sérgio Luiz Pinheiro ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Antigen Presenting Cells ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Inflammatory Immune Response ◽  
Antigen Presenting ◽  
The Relationship

Leptin is a hormone synthesized predominantly by white adipose tissue. Its production levels are directly proportional to the total mass of this tissue in an individual’s body. Apart from its classic role in the regulation of hunger and satiety, it also plays an important part in scenarios involving innate and adaptive immune responses. It has been discovered that leptin levels are altered in a variety of inflammatory responses, such as periodontitis, a condition which derives from a persistent inflammatory immune response from a host facing bacterial infection. The initial trigger for this reaction is the recognition of the pathogens by antigen presenting cells, such as macrophages and dendritic cells, whose actions can be influenced by leptin. This review aims to present the relationship between leptin, dendritic cells and macrophages in the context of periodontal disease. Thus, we have assembled the most important findings related to leptin’s role in the modulation of the immune response carried out by these cells in periodontitis.

scholarly journals Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

2021 ◽  
Vol 12 ◽  
Author(s):  
Haixia Li ◽  
Shan Liu ◽  
Jinming Han ◽  
Shengxian Li ◽  
Xiaoyan Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Toll Like Receptors ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Partial Activation

Toll-like receptors (TLRs) are a class of proteins playing a key role in innate and adaptive immune responses. TLRs are involved in the development and progression of neuroimmune diseases via initiating inflammatory responses. Thus, targeting TLRs signaling pathway may be considered as a potential therapy for neuroimmune diseases. However, the role of TLRs is elusive and complex in neuroimmune diseases. In addition to the inadequate immune response of TLRs inhibitors in the experiments, the recent studies also demonstrated that partial activation of TLRs is conducive to the production of anti-inflammatory factors and nervous system repair. Exploring the mechanism of TLRs in neuroimmune diseases and combining with developing the emerging drug may conquer neuroimmune diseases in the future. Herein, we provide an overview of the role of TLRs in several neuroimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barré syndrome and myasthenia gravis. Emerging difficulties and potential solutions in clinical application of TLRs inhibitors will also be discussed.

Limonin Modulated Immune and Inflammatory Responses to Suppress Colorectal Adenocarcinoma in Mice Model

2021 ◽  
Author(s):  
Nur Iliyani Mohd Ishak ◽  
SUHAILA MOHAMED ◽  
Iffah Nadhira Madzuki ◽  
Noordin Mohamed Mustapha ◽  
Norhaizan Mohd Esa
Keyword(s):  
Colorectal Cancer ◽  
Immune Responses ◽  
Prostaglandin E2 ◽  
Inflammatory Responses ◽  
Mice Model ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Mrna Expression Analysis ◽  
Healthy Control

Abstract Purpose. Inflammation and compromised immune responses often increases colorectal cancer (CRC) risk. The immune-modulating effects of limonin on carcinogen/inflammation-induced colorectal cancer (CRC) were studied in mice. Methods: Male Balb/c mice were randomly assorted into three groups (n=6): healthy control, non-treated CRC-induced (azoxymethane/dextran-sulfate-sodium AOM/DSS) control, and CRC-induced+50 mg limonin /kg body-weight. The CRC development were monitored via macroscopic, histopathological, ELISA and mRNA expression analysis. Results: Limonin downregulated inflammation (TNF-α, tumor necrosis factor-α), enhanced the adaptive immune responses (CD8, CD4, and CD19), and upregulated antioxidant defense (Nrf2, SOD2) mRNA expressions. Limonin reduced serum malondialdehyde (MDA, lipid peroxidation biomarker), prostaglandin-E2 and histopathology inflammation scores, while increasing reduced-glutathione (GSH) in the CRC-induced mice. Limonin significantly (p<0.05) increased T cells (CD4 and CD8) and B cells (CD19) in spleen tissues. The CD335 (natural killer cells) were increased in the CRC-induced mice and limonin treatment restored it to normal levels suggesting reinstatement to normal colon conditions.Conclusion: Limonin apparently mitigated CRC development, by ameliorating adaptive immune responses (CD8, CD4, and CD19), reducing inflammation (serum prostaglandin-E2; TNF-α, innate immune responses), oxidative stress and enhancing the endogenous anti-oxidation defense reactions (GSH) in the CRC-induced mice.

scholarly journals Nrf2 Is Crucial to Graft Survival in a Rodent Model of Heart Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Wu ◽  
Quan Qiu ◽  
Huihui Wang ◽  
Samantha A. Whitman ◽  
Deyu Fang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Immune Responses ◽  
Graft Survival ◽  
Immune Cells ◽  
Mrna Levels ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Survival Pathways ◽  
Patients With Heart Failure

Currently, the sole treatment option for patients with heart failure is transplantation. The battle of prolonging graft survival and modulating innate and adaptive immune responses is still being waged in the clinic and in research labs. The transcription factor Nrf2 controls major cell survival pathways and is central to moderating inflammation and immune responses. In this study the effect of Nrf2 levels in host recipient C57BL/6 mice on Balb/c allogeneic graft survival was examined. Importantly, Nrf2−/−recipient mice could not support the graft for longer than 7.5 days on average, whereas activation of Nrf2 by sulforaphane in Nrf2+/+hosts prolonged graft survival to 13 days. Several immune cells in the spleen of recipient mice were unchanged; however, CD11b+macrophages were significantly increased in Nrf2−/−mice. In addition, IL-17 mRNA levels were elevated in grafts transplanted into Nrf2−/−mice. Although Nrf2 appears to play a crucial role in graft survival, the exact mechanism is yet to be fully understood.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechrs ◽  
Maria Litovchenko ◽  
Marjan Biočanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Abstract Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechers ◽  
Maria Litovchenko ◽  
Marjan Biocanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

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