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IL-17–expressing CD4 + T lymphocytes (Th17 cells) naturally reside in the intestine where specific cytokines and microbiota, such as segmented filamentous bacteria (SFB), promote their differentiation. Intestinal Th17 cells are thought to initially differentiate in the GALT and/or mesenteric lymph nodes upon Ag encounter and subsequently home to th...
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... Similarly, ILC3-derived IL-22 can play a beneficial role by enhancing barrier function and aiding in mucosal healing. 75 Investigations of bacterial sensing in the intestine have established that the responsiveness of macrophages and DCs can be controlled by unique bacteria-derived signals (Figure 3). Much of the evidence in this area stems from studies using germ-free mice colonized with different bacteria or bacterial by-products. ...
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... If the microorganisms persist, these cells can display peptides processed via major histocompatibility complexes I or II (MHCI or MHCII) to TCD4 or TCD8 lymphocytes. When these cells are activated, they secrete cytokines such as IL-2, which promote lymphocyte proliferation and differentiation [23]. Subsequently, they secrete interferon-gamma (IFN-γ), which enables them to exert the effector functions of MØ for the elimination of pathogens. ...
Lactoferrin (LF) is a glycoprotein that binds to iron ions (Fe2+) and other metallic ions, such as Mg2+, Zn2+, and Cu2+, and has antibacterial and immunomodulatory properties. The antibacterial properties of LF are due to its ability to sequester iron. The immunomodulatory capability of LF promotes homeostasis in the enteric environment, acting directly on the beneficial microbiota. LF can modulate antigen-presenting cell (APC) biology, including migration and cell activation. Nonetheless, some gut microbiota strains produce toxic metabolites, and APCs are responsible for initiating the process that inhibits the inflammatory response against them. Thus, eliminating harmful strains lowers the risk of inducing chronic inflammation, and consequently, metabolic disease, which can progress to type 2 diabetes mellitus (T2DM). LF and retinoic acid (RA) exhibit immunomodulatory properties such as decreasing cytokine production, thus modifying the inflammatory response. Their activities have been observed both in vitro and in vivo. The combined, simultaneous effect of these molecules has not been studied; however, the synergistic effect of LF and RA may be employed for enhancing the secretion of humoral factors, such as IgA. We speculate that the combination of LF and RA could be a potential prophylactic alternative for the treatment of metabolic dysregulations such as T2DM. The present review focuses on the importance of a healthy diet for a balanced gut and describes how probiotics and prebiotics with immunomodulatory activity as well as inductors of differentiation and cell proliferation could be acquired directly from the diet or indirectly through
the oral administration of formulations aimed to maintain gut health or restore a eubiotic state in an intestinal environment that has been dysregulated by external factors such as stress and a high-fat diet.
... Importantly, it has been demonstrated that goblet cells can transport luminal antigens to underlying lamina propria DCs [26]. Residential macrophages of the lamina propria support tolerance to gut microbiota dependent on routine sensing, responsiveness to IL-10, and the presence of TGFβ to induce FoxP3 + Tregs [27]. These resident intestinal macrophages remain refractory to inflammatory stimuli and present antigens via MHC II to promote tolerance. ...
... These inflammatory macrophages recognize and eliminate pathogens, such as invading bacteria, that translocate past the epithelium via strong bactericidal activity and clearance by phagocytosis. Intestinal macrophages also produce pro-inflammatory cytokines IL-1, IL-6, and TNF and express costimulatory molecules, such as CD40 [27]. ...
Crohn’s disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy. In this review, the role of altered autophagy in the mucosal innate immune response in the context of CD is discussed, with a specific focus on dendritic cells, macrophages, Paneth cells, and goblet cells. Selective autophagy, such as xenophagy, ERphagy, and mitophagy, that play crucial roles in maintaining intestinal homeostasis in these innate immune cells, are discussed. As our understanding of autophagy in CD pathogenesis evolves, the development of autophagy-targeted therapeutics may benefit subsets of patients harboring impaired autophagy.
... Cecal tonsils are located at the cecum-rectum junction and have a structure similar to Peyer's patches 20,21 . Antigen recognition through M cells or by direct antigen sampling by macrophages and dendritic cells induce intestinal immune responses 22,23 . ...
Poultry infection with avian influenza viruses (AIV) is a continuous source of concern for poultry production and human health. Uncontrolled infection and transmission of AIV in poultry increases the potential for viral mutation and reassortment, possibly resulting in the emergence of zoonotic viruses. To this end, implementing strategies to disrupt the transmission of AIVs in poultry, including a wide array of traditional and novel methods, is much needed. Vaccination of poultry is a targeted approach to reduce clinical signs and shedding in infected birds. Strategies aimed at enhancing the effectiveness of AIV vaccines are multi-pronged and include methods directed towards eliciting immune responses in poultry. Strategies include producing vaccines of greater immunogenicity via vaccine type and adjuvant application and increasing bird responsiveness to vaccines by modification of the gastrointestinal tract (GIT) microbiome and dietary interventions. This review provides an in-depth discussion of recent findings surrounding novel AIV vaccines for poultry, including reverse genetics vaccines, vectors, protein vaccines and virus like particles, highlighting their experimental efficacy among other factors such as safety and potential for use in the field. In addition to the type of vaccine employed, vaccine adjuvants also provide an effective way to enhance AIV vaccine efficacy, therefore, research on different types of vaccine adjuvants and vaccine adjuvant delivery strategies is discussed. Finally, the poultry gastrointestinal microbiome is emerging as an important factor in the effectiveness of prophylactic treatments. In this regard, current findings on the effects of the chicken GIT microbiome on AIV vaccine efficacy are summarized here.
... 19 Similarly, recruited monocytes are a significant source of pro-inflammatory cytokines including IL-1β, TNF, IL-12 and IL-6. 19,[21][22][23][24] We found that CoPP treatment resulted in dual protective mechanisms in colitis. ...
Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis. Surprisingly, conditional deletion of myeloid HO-1 did not impact the colonic inflammatory response or the protective influence of CoPP in the setting of dextran sodium sulfate-induced colitis. Rather, we reveal that CoPP elicits a contradictory shift in blood myeloid populations relative to the colon during active intestinal inflammation. Major population changes include markedly diminished trafficking of CCR2⁺Ly6Chi monocytes to the inflamed colon, despite significant mobilization of this population into circulation. This resulted in significantly diminished colonic expansion of monocyte-derived macrophages and inflammatory cytokine expression. These findings were linked with significant induction of systemic CCL2 leading to a disrupted CCL2 chemoattractant gradient toward the colon and concentration-dependent suppression of circulating monocyte CCR2 expression. Administration of CoPP also induced macrophage differentiation toward a MarcohiHmox1hi anti-inflammatory erythrophagocytic phenotype, contributing to an overall decreased inflammatory profile. Such findings redefine protective influences of heme metabolism during inflammation, and highlight previously unreported immunosuppressive mechanisms of endogenous CCL2 induction.
... Cecal tonsils are located at the cecum-rectum junction and have a structure similar to Peyer's patches 20,21 . Antigen recognition through M cells or by direct antigen sampling by macrophages and dendritic cells induce intestinal immune responses 22,23 . ...
Influenza viruses cause severe respiratory infections in humans and birds, triggering global health concerns and economic burden. Influenza infection is a dynamic process involving complex biological host responses. The objective of this study was to illustrate global biological processes in ileum and cecal tonsils at early time points after chickens were infected with low pathogenic avian influenza virus (LPAIV) H9N2 through transcriptome analysis. Total RNA isolated from ileum and cecal tonsils of non-infected and infected layers at 12-, 24- and 72-h post-infection (hpi) was used for mRNA sequencing analyses to characterize differentially expressed genes and overrepresented pathways. Statistical analysis highlighted transcriptomic signatures significantly occurring 24 and 72 hpi, but not earlier at 12 hpi. Interferon (IFN)-inducible and IFN-stimulated gene (ISG) expression was increased, followed by continued expression of various heat-shock proteins (HSP), including HSP60, HSP70, HSP90 and HSP110. Some upregulated genes involved in innate antiviral responses included DDX60, MX1, RSAD2 and CMPK2. The ISG15 antiviral mechanism pathway was highly enriched in ileum and cecal tonsils at 24 hpi. Overall, most affected pathways were related to interferon production and the heat-shock response. Research on these candidate genes and pathways is warranted to decipher underlying mechanisms of immunity against LPAIV in chickens.
... The intestine is the most dynamic and the largest compartment of the immune system where nutrient digestion and absorption take place. Moreover, it plays a critical role in host immunity to maintain intestinal homeostasis through several interactions between immune cells and microbes, and the immune cells actively monitor, recognize, and differentiate food antigens from external antigens including pathogens [14]. Thus, many studies have attempted to modulate the intestinal immune system by employing immunostimulants (or immune modulators). ...
Fucoidans are cell wall polysaccharides found in various species of brown seaweeds. They are fucose-containing sulfated polysaccharides (FCSPs) and comprise 5-20% of the algal dry weight. Fucoidans possess multiple bioactivities, including antioxidant, anticoagulant, antithrombotic, anti-inflammatory, antiviral, anti-lipidemic, anti-metastatic, anti-diabetic and anti-cancer effects. Dietary fucoidans provide small but constant amounts of FCSPs to the intestinal tract, which can reorganize the composition of commensal microbiota altered by FCSPs, and consequently control inflammation symptoms in the intestine. Although the bioactivities of fucoidans have been well described, there is limited evidence to implicate their effect on gut microbiota and bowel health. In this review, we summarize the recent studies that introduce the fundamental characteristics of various kinds of fucoidans and discuss their potential in altering commensal microorganisms and influencing intestinal diseases.
... In mice, IgA-coated commensal organisms can be taken up by M cells in the Peyer's patches of the small intestine and presented to underlying dendritic cells to elicit production of immunosuppressive IL-10 and stimulation of Tregs, thereby maintaining antigen-specific, commensaltargeted homeostasis [35,36]. Non-activated dendritic cells migrating to regional lymph nodes also secrete retinoic acid and TGF-β, leading to differentiation of naïve T cells into tolerogenic Tregs expressing gut-homing α4β7 and CCR9 surface markers that facilitate maintenance of gut homeostasis [28,31,37,38]. These Tregs secrete TGF-β and IL-10 to suppress Th17 cells and inflammation [26,39]. ...
: The use of live-attenuated bacterial vaccines as carriers for the mucosal delivery of foreign antigens to stimulate the mucosal immune system was first proposed over three decades ago. This novel strategy aimed to induce immunity against at least two distinct pathogens using a single bivalent carrier vaccine. It was first tested using a live-attenuated Salmonella enterica serovar Typhi strain in clinical trials in 1984, with excellent humoral immune responses against the carrier strain but only modest responses elicited against the foreign antigen. Since then, clinical trials with additional Salmonella-based carrier vaccines have been conducted. As with the original trial, only modest foreign antigen-specific immunity was achieved in most cases, despite the incorporation of incremental improvements in antigen expression technologies and carrier design over the years. In this review, we will attempt to deconstruct carrier vaccine immunogenicity in humans by examining the basis of bacterial immunity in the human gastrointestinal tract and how the gut detects and responds to pathogens versus benign commensal organisms. Carrier vaccine design will then be explored to determine the feasibility of retaining as many characteristics of a pathogen as possible to elicit robust carrier and foreign antigen-specific immunity, while avoiding over-stimulation of unacceptably reactogenic inflammatory responses.
... In addition, pathways activated by Prevotella have been elucidated preliminarily. It has been demonstrated that in response to bacterial contact, DCs are activated to secrete cytokines driving the unique differentiation and expansion of the CD4 + T cell in the intestine [44,45]. Such in vivo conditioning of DCs by bacteria appears to extend outside the intestine such as BMDCs [46]. ...
Th17-mediated mucosal inflammation is related to increased Prevotella bacterial abundance. The actual involvement of Prevotella in the development and accumulation of intestinal Th17 cells at a steady state, however, remains undefined. Herein, we investigated the role of Prevotella in inducing intestinal Th17 cells in mice. Mice were treated with a combination of broad-spectrum antibiotics (including ampicillin, neomycin sulfate, vancomycin hydrochloride, and metronidazole) in their drinking water for 4 weeks and then gavaged with Prevotella for 4 weeks. After inoculation, 16S rDNA sequencing was used to verify the colonization of Prevotella in the colon of mice. The IL-17A as well as IL-17A-expressing T cells was localized and quantified by an immunofluorescence assay (IFA) of colon sections. Th17 cells in the mesenteric lymph nodes of mice were counted by flow cytometry. Systemic immune response to Prevotella colonization was evaluated based on the serum levels of IL-6, TNF-α, IL-1β, IL-17A, IL-10, IL-4, IFN-γ, and IL-2. Th17-polarizing cytokines (IL-6, TNF-α, IL-1β, and IL-2) induced by Prevotella were evaluated by stimulation of bone marrow-derived dendritic cells (BMDCs). Results revealed that after inoculation, Prevotella successfully colonized the intestine of mice and induced the production and accumulation of colonic Th17 cells in the colon. Moreover, Prevotella elevated some of the Th17-related cytokines in the serum of mice. And Th17-polarizing cytokines (IL-6 and IL-1β) produced by BMDCs were mediated mainly through the interaction between Prevotella and Toll-like receptor 2 (TLR2). In conclusion, our data suggest that Prevotella induces the production of Th17 cells in the colon of mice, thus highlighting the potential role of Prevotella in training the intestinal immune system.
... Intestinal macrophages and other immune cells are supported by mucins and antimicrobial peptides which are secreted by goblet and Paneth cells in the intestinal epithelium to trap and oppose harmful bacteria [11]. Within the lamina propria, there are cells of the myeloid lineage which sense foreign antigens, either in lymphoid follicles beneath the follicle-associated epithelium or also along the normal villous epithelium [12]. They present foreign antigens to T-and B-lymphocytes, which subsequently induce a specific immune response to eliminate invading pathogens and to mediate antibody production [13][14][15]. ...
Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
... Besides this, the intestinal antigen-presenting cells (APC), predominantly composed of macrophages and dendritic cells, play a central role in initiating and orchestrating immune responses. At homeostasis, they participate in the tolerance towards dietary components and colonizing commensal microbiota, but they also have the ability to fight pathogens [3]. ...
The early life period is crucial for the maturation of the intestinal barrier, its immune system, and a lifelong beneficial host-microbiota interaction. The study aims to assess the impact of a beneficial dietary (short-chain fructooligosaccharides, scFOS) supplementation vs. a detrimental dietary environment (such as mycotoxin deoxynivalenol, DON) on offspring intestinal immune system developmental profiles. Sows were given scFOS-supplemented or DON-contaminated diets during the last 4 weeks of gestation, whereas force-feeding piglets with DON was performed during the first week of offspring life. Intestinal antigen-presenting cell (APC) subset frequency was analyzed by flow cytometry in the Peyer's patches and in lamina propria and the responsiveness of intestinal explants to toll-like receptor (TLR) ligands was performed using ELISA and qRT-PCR from post-natal day (PND) 10 until PND90. Perinatal exposure with scFOS did not affect the ontogenesis of APC. While it early induced inflammatory responses in piglets, scFOS further promoted the T regulatory response after TLR activation. Sow and piglet DON contamination decreased CD16+ MHCII+ APC at PND10 in lamina propria associated with IFNγ inflammation and impairment of Treg response. Our study demonstrated that maternal prebiotic supplementation and mycotoxin contamination can modulate the mucosal immune system responsiveness of offspring through different pathways.
