Lamina Propria Macrophages Research Articles

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson’s disease

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson’s disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

Excess of circulating apotransferrin enhances dietary iron absorption in mice

AbstractIntravenous injection of excess apotransferrin enhances dietary iron absorption in mice and triggers accumulation of plasma non–transferrin-bound iron. Injected fluorescent-labeled transferrin colocalizes with lamina propria macrophages, consistent with the recently proposed iron absorption checkpoint involving macrophage-mediated transferrin degradation.

Effects and mechanisms of Salmonella plasmid virulence gene spv on host-regulated cell death.

Salmonella is responsible for the majority of food poisoning outbreaks around the world. Pathogenic Salmonella mostly carries a virulence plasmid that contains the Salmonella plasmid virulence gene (spv), a highly conserved sequence encoding effector proteins that can manipulate host cells. Intestinal epithelial cells are crucial components of the innate immune system, acting as the first barrier of defense against infection. When the barrier is breached, Salmonella encounters the underlying macrophages in lamina propria, triggering inflammation and engaging in combat with immune cells recruited by inflammatory factors. Host regulated cell death (RCD) provides a variety of means to fight against or favour Salmonella infection. However, Salmonella releases effector proteins to regulate RCD, evading host immune killing and neutralizing host antimicrobial effects. This review provides an overview of pathogen-host interactions in terms of (1) pathogenicity of Salmonella spv on intestinal epithelial cells and macrophages, (2) mechanisms of host RCD to limit or promote pathogenic Salmonella expansion, and (3) effects and mechanisms of Salmonella spv gene on host RCD.

Colonic mucosa barrier defects in collagenous and ischemic colitis.

The subepithelial myofibroblasts (SEMFs) and the subepithelial band of macrophages (SEBM) are major components of the colonic mucosa barrier. Although their role in homeostasis is widely recognized, their contribution to disease states is largely unknown. Our aim was to explore histological characteristics of SEMFs and SEBM in collagenous and ischemic colitis in order to identify specific changes in distinct mucosa backgrounds lacking significant inflammation. SEMFs, SEBM and lamina propria (LP) macrophages were identified immunohistochemically by alpha smooth muscle Actin and Cluster of Differentiation 68 respectively in 38 colonic biopsies [14 collagenous colitis (CC), 14 ischemic colitis (IC), 10 normal mucosa]. In CC, SEMFs were rarely detectable in the collagenous band while aSMA-negative pericryptal fibroblast-like cells appeared. In lower LP interconnecting SEMFs processes were formed. SEBM was preserved in areas with a collagenous layer up to 20 μm. In thicker layers, it was fragmented and gradually disappeared in parallel with engulfment of enlarged macrophages. LP macrophages were usually increased. In IC, slight SEMFs changes preceded discernible epithelial alterations. Rounding, disintegration and extinction of SEMFs constituted successive alterations coinciding with crypt shrinkage and denudation. SEBM displayed total or almost total abolishment in areas with crypt damage but also in sites with minimal changes and in adjacent normal mucosa. Our findings provide evidence of impairment of both mucosa barrier constituents in CC and IC. In CC, histological alterations are closely related to the collagenous layer which seems to affect SEMFs differentiation and migration as well as SEBM integrity. The early extinction of SEBM in IC is indicative of its high sensitivity to hypoxia and hypoperfusion.

Anion‐Dependent Layered Double Hydroxide Nanoparticles Regulate Differentiation of CD206+ CX3CR1+ Macrophages by Inhibiting the IL‐17 Signaling Pathway Contributing to Inflammatory Bowel Disease

AbstractInflammatory bowel disease (IBD) is a chronic and destructive autoimmune disease that has created a global burden. However, the pathogenesis and treatment strategies of IBD remain difficult problems to overcome. The anti‐inflammatory action of anion‐dependent layered double hydroxide (LDH) is evaluated in IBD. Raw264.7 macrophages induced by Lipopolysaccharide (LPS) produced low levels of pro‐inflammatory cytokines after LDH treatment. The results from dextran sulfate sodium (DSS)‐induced murine colitis models show that LDHs significantly reduce pro‐inflammatory cytokines in the colon tissue and inhibit colon atrophy. Most importantly, LDH with NO3− as the interlayer anion (LDH‐NO3−) demonstrates superior anti‐inflammatory ability compared to LDH with Cl− as the interlayer anion (LDH‐Cl−), both in vitro and in vivo. LDH‐NO3− promotes the differentiation of CD206+CX3CR1+ lamina propria macrophages, reduces the abundance of T helper 17 (Th17) cells, and inhibits the activation of the IL‐17 signaling pathway. LDH‐NO3− also limits the pro‐inflammatory effects of IL‐17A on macrophages, and the anti‐inflammatory effects of LDH‐NO3− are reversed by IL‐17RA‐siRNA. Suggesting that LDH effectively inhibits the inflammatory reaction induced by the interaction between macrophages and Th17 cells. This study demonstrates that LDH‐NO3− is a drug‐free nanomedicine that acts against IBD, providing application prospects for LDH‐NO3− in IBD treatment.

Macrophage polarization toward M1 phenotype in T cell transfer colitis model

BackgroundT cell transfer colitis model is often used to study the CD4+ T cell functions in the intestine. However, the specific roles of macrophages in colitis remain unclear. In this study, we aimed to evaluate the phenotype and functions of macrophages in the colonic lamina propria (LP) in a colitis model.MethodsColitis was induced in scid mice via the adaptive transfer of CD4+CD45RBhi T cells. Then, flow cytometry was used to determine the number of macrophages in the colonic LP and expression of cytokines in macrophages at the onset of colitis. Moreover, M1/M2 macrophage markers were detected in the colonic LP during colitis development using high-dimensional single-cell data and gating-based analyses. Expression levels of M1 markers in macrophages isolated from the colonic LP were measured using quantitative reverse transcription-polymerase chain reaction. Additionally, macrophages were co-cultured with T cells isolated from the colon to assess colitogenic T cell activation.ResultsInfiltration of macrophages into the colon increased with the development of colitis in the T cell transfer colitis model. M1/M2 macrophage markers were observed in this model, as observed in the colon of patients with inflammatory bowel disease (IBD). Moreover, number of M1 macrophages increased, whereas that of M2 macrophages decreased in the colonic LP during colitis development. M1 macrophages were identified as the main source of inflammatory cytokine production, and colitogenic T cells were activated via interactions with these macrophages.ConclusionsOur findings revealed that macrophages polarized toward the M1 phenotype in LP during colitis development in the T cell transfer colitis model. Therefore, the colitis model is suitable for the evaluation of the efficacy of macrophage-targeted drugs in human IBD treatment. Furthermore, this model can be used to elucidate the in vivo functions of macrophages in the colon of patients with IBD.

ASTRAGALOSIDE Ⅳ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS.

M1 macrophage-mediated inflammation is critical in sepsis. We previously found the protective role of astragaloside intravenous (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFAs) in septic gut damage. Mice were pretreated by AS-IV gavage for 7 days before cecal ligation and puncture. M1 polarization of gut lamina propria macrophages (LpMs) was promoted by cecal ligation and puncture, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate, and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome, and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation or exogenous butyrate supplementation. In Caco-2 and THP-1 cocultured model, LPS and interferon γ caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release, and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study

BackgroundAlthough asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC).MethodsEBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9.ResultsThe tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups.ConclusionThese results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity

Little is known about the effects of high-fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1hiMHCIIhi and were CD4-TIM4-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid-associated macrophages (LAMs). Via single-cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HFD, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis, and efferocytosis signatures. CX3CR1hiMHCIIhi colonic resident LPMs had fewer lipid droplets (LDs) and decreased triacylglycerol (TG) content compared to equivalent cells in lean mice and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.

The role of type II esophageal microbiota in achalasia: Activation of macrophages and degeneration of myenteric neurons

ObjectiveThe gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility disorder characterized by the selective degeneration of inhibitory neurons in the esophageal myenteric plexus. This study aimed to evaluate the composition of the esophageal microbiota in achalasia and explore the potential microbial mechanisms involved in its pathogenesis. DesignThe lower esophageal mucosal microbiota was analyzed in patients with achalasia and control participants using 16 S rRNA sequencing. The association between the esophageal microbiota and achalasia was validated by inducing esophageal dysbiosis in C57BL/10 J and C57BL/10ScNJ (TLR4KO) mice via chronic exposure to ampicillin sodium in their drinking water. ResultsThe esophageal microbiota in EA patients had lower diversity and a predominance of Gram-negative bacteria (Type II microbiota) compared to that in the healthy controls. Additionally, the relative abundance of Rhodobacter decreased significantly in patients with achalasia, which correlated with an enrichment of lipopolysaccharide (LPS) biosynthesis based on the COG database. Antibiotic-treated mice showed an esophageal microbiota characterized by increased abundance of Gram-negative bacteria (Type II microbiome), decreased abundance of Rhodobacter, and enriched LPS biosynthesis. Compared to the control and TLR4KO mice, the antibiotic-treated wild-type mice had higher LES resting pressure, increased LES contraction rate after carbachol stimulation, and decreased relaxation response to L-arginine. Moreover, the number of myenteric neurons decreased, while the number of lamina propria macrophages (LpMs) increased after antibiotic exposure. Furthermore, the TLR4-MYD88-NF-κB pathway was up-regulated, and the production of TNF-α, IL-1β, and IL-6 increased in the antibiotic-treated mice. ConclusionsPatients with achalasia exhibit esophageal dysbiosis, which may induce aberrant esophageal motility.

Systemic salmonellosis in 4 cats.

Clinical signs in 4 cases of salmonellosis in cats included vomiting, diarrhea (2 cases each), fever, dystocia, icterus, and seizures (1 case each). Three cats died, and one was euthanized. Grossly, all cats were in poor body condition and had yellow-to-dark-red perianal feces (3 cases), oral and ocular pallor (2 cases) or icterus (1 case), fluid or pasty yellow intestinal contents (4 cases), white or dark-red-to-black depressed areas on the hepatic surface (2 cases), yellow abdominal fluid with swollen abdominal lymph nodes (1 case), and fibrin strands on the placental chorionic surface (1 case). Histologically, all cats had necrotizing enterocolitis and random hepatocellular necrosis. Other histologic findings included mesenteric (4 cases) or splenic (2 cases) lymphoid necrosis, and endometrial and chorioallantoic necrosis (1 case). Gram-negative bacilli were observed within neutrophils and macrophages in the intestinal lamina propria (4 cases), liver, spleen, lymph node, endometrium, and placenta (1 case each). Aerobic bacterial culture on frozen samples of small intestine, mesenteric lymph node, lung, and liver yielded Salmonella enterica subsp. enterica. Serotyping was consistent with S. Enteritidis (cases 1, 3) and S. Typhimurium (cases 2, 4).

Selenoprotein W Ameliorates Experimental Colitis and Promotes Intestinal Epithelial Repair.

Selenoprotein W (Selenow) is a ~9 kDa selenoprotein suggested to play a beneficial role in resolving inflammation. However, the underlying mechanisms are poorly understood. SELENOW expression in the human GI tract using ScRNAseq Gut Cell Atlas and Gene Expression Omnibus (GEO) databases revealed its expression in the small intestine and colonic epithelial, endothelial, mesenchymal, and stem cells and correlated with a protective effect in ulcerative colitis patients. Selenow KO mice treated with 4% dextran sodium sulfate (DSS) showed exacerbated acute colitis, with greater weight loss, shorter colons, and increased fecal occult blood compared to the WT counterparts. Selenow KO mice expressed higher colonic Tnfα, increased Tnfα+ macrophages in the colonic lamina propria, and exhibited loss in epithelial barrier integrity and decreased zonula occludens 1 (Zo-1) expression following DSS treatment. Expression of epithelial cellular adhesion marker (EpCam), yes-associated protein 1 (Yap1), and epidermal growth factor receptor (Egfr) were decreased along with CD24lo cycling epithelial cells in Selenow KO mice. Colonic lysates and organoids confirmed a crosstalk between Egfr and Yap1 that was regulated by Selenow. Overall, our findings suggest Selenow expression is key for efficient resolution of inflammation in experimental colitis that is mediated through the regulation of Egfr and Yap1.

P230 Adalimumab in Crohn’s disease is protective against periodontitis based on a validated oral health questionnaire

Abstract Background Crohn’s disease (CD) is associated with a 3-4 fold increased risk of periodontitis compared to the general population1 though periodonitis is poorly recognised and diagnosed. Evidence from mouse models highlight an important link between oral and gut health. Periodontitis has been shown to lead to ectopic colonization of oral pathogens and oral Th17-T cells that activate lamina propria macrophages and exacerbate gut inflammation2. Very little is known about the patient demographics of those at risk of periodontitis. This study aimed to assess the risk factors for periodontitis in CD patients. Methods We conducted a cross-sectional study recruiting CD patients at UCLH through myCare, an online platform for patients linked to their clinical records. Patient data were obtained using EpicCare, a web-based electronic patient record database. Patient risk of periodontitis was determined using a previously validated oral health questionnaire3. Statistical tests were conducted using IBM SPSS Statistics 27. Results This single centre study included 89 CD patients; 54% female and median age of 40 (IQR 19-82). Patients predominantly identified as White British (56%). The majority had ileocolonic CD (51%) with non-stricturing/non-penetrating behaviour (70%) and were on biologic therapy (52%) (Tab 1). The oral health questionnaire identified 37% of CD patients at risk of periodontitis. There was no statistically significant association between periodontitis risk and age, gender, age at CD diagnosis, disease duration, CD phenotype, family history, body mass index (BMI) or smoking status. Current steroid, immunomodulator use and number of prior biologics also showed no association. Current use of adalimumab and ustekinumab were both independently correlated with risk of periodontitis (χ2 p=0.004 &amp; χ2 p=0.044, respectively). 90% of patients receiving adalimumab were not at risk of periodontitis (Fig 1). In contrast, 60% of patients on ustekinumab were at risk of periodontitis. Logistic regression analysis showed that patients receiving adalimumab were 86% less likely to be at risk of periodontitis compared to patients not receiving adalimumab (OR 0.14 (CI 0.029 - 0.633, p=0.011)). 75% of the adalimumab group was anti-TNF naïve, but no association was seen between prior biologic use and periodontitis risk (p=0.91). Conclusion The questionnaire has identified a third of patients who are at risk of periodontitis in the CD cohort. Adalimumab shows benefit in mitigating this risk and may be a drug of choice in patients with oral disease. The questionnaire is a helpful tool to identify and refer at-risk patients.

Changes of intestinal wall barrier function and its correlation with susceptibility to infection in patients with cirrhotic portal hypertension

Objective: To investigate the changes of intestinal wall barrier function and its correlation with infection occurrence in patients with cirrhotic portal hypertension. Methods: 263 patients with cirrhotic portal hypertension were split into: the clinically evident portal hypertension (CEPH) combined with infection group (n = 74); CEPH group (n = 104); and Non-CEPH group (n = 85). Among them, 20 CEPH patients and 12 non-CEPH patients in non-infection status were subjected to sigmoidoscopy. Immunohistochemical staining was used to detect the expression of trigger receptor-1 (TREM-1), CD68, CD14, the inducible nitric oxide synthase molecule, and Escherichia coli (E.coli) in the medullary cells of the colon mucosa. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of soluble myeloid cell trigger receptor-1 (sTREM-1), soluble leukocyte differentiation antigen-14 subtype (sCD14-ST) and intestinal wall permeability index enteric fatty acid binding protein (I-FABP). Fisher's exact probability method, one-way ANOVA, Kruskal-Wallis-H test, Bonferroni method, and Spearman correlation analysis were used for statistical analysis. Results: The serum sTREM-1 and I-FABP levels were higher in CEPH patients than those of non-CEPH patients in the non-infectious state (P < 0.05), but the difference in blood sCD14-ST levels was not statistically significant (P > 0.05). Serum levels of sTREM-1, sCD14-ST, and I-FABP in infected patients were higher than those in patients without a concurrent infection (P < 0.05). Serum sCD14-ST levels were positively correlated with serum sTREM-1, C-reactive protein (CRP), and procalcitonin (PCT), and sTREM-1 levels were also positively correlated with CRP and PCT (r > 0.5, P < 0.001). The rates of CD68, inducible nitric oxide synthase, CD14-positive cells, and E.coli-positive glands were higher in the intestinal mucosa of the CEPH group than those of the control group (P < 0.05). Spearman's correlation analysis showed that the rate of E.coli-positive glands in CEPH patients was positively correlated with the expression of molecular markers CD68 and CD14 in the lamina propria macrophages. Conclusion: Patients with cirrhotic portal hypertension have increased intestinal permeability and inflammatory cells, accompanied by bacterial translocation. Serum sCD14-ST and sTREM-1 can be used as indicators to predict and evaluate the occurrence of infection in patients with cirrhotic portal hypertension.

MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway

Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg–1·d–1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CRint proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.

Histological study on regional specificity of the mucosal nerve network in the rat large intestine.

Our previous studies and others have revealed detailed characteristics of the mucosal nerve network in the small intestine, but much remains unknown about the corresponding network in the large intestine. We herein investigated regional differences in the expression of neurochemical markers, the nerve network structure, and the cells in contact with nerve fibers by histological analysis using both immunohistochemistry and serial block-face scanning electron microscopy (SBF-SEM). Immunohistochemistry revealed that immunopositive structures for protein gene product 9.5, vasoactive intestinal peptide (VIP), calretinin and vesicular acetylcholine transporter were more prevalent in the lamina propria of the ascending colon than the cecum and descending colon (DC). There was no significant difference in the frequency of most neurochemical markers between the cecum and DC, but the frequencies of VIP+ structures were higher in the cecum than in the DC. SBF-SEM analysis showed that the nerve network structure was more developed on the luminal side of the DC than the cecum. The cells that nerve fibers abundantly contacted were subepithelial and lamina propria fibroblast-like cells and macrophages. In addition, nerve fibers in the cecum were in more frequent contact with immune cells such as macrophages and plasma cells than nerve fibers in the DC. Thus, the present histological analysis suggested that the mucosal nerve network in the large intestine possessed both regional universality and various specificities, and revealed the intimate relationship between the nerve network and immune cells, especially in the cecum.

THE NUMBER OF MAST CELLS AND MACROPHAGES IN CHRONIC GINGIVAL INFLAMMATION IN YOUNG PEOPLE

The aim of this work was to study the number of mast cells and macrophages of the gingival lamina propria in young people in chronic inflammation. as a result of the study, new data were obtained on the distribution of mast cells and macrophages in the gum without inflammation. It is for the first time that the effect of microbial inflammation and laser therapy on resident cells of the connective gingival tissue is studied, those cells are part of the oral mucosal immune system, depending on the age. Gingival biopsy material obtained according to dental indications in patients aged 20–40 years was used in the work. CD68+ macrophages were detected by immunohistochemical method, the number and secretory activity of gingival mast cells were evaluated by staining with toluidine blue. The results of the conducted examinations showed that in parodontitis, the number of macrophages and degranulating mast cells in the connective tissue of the gingival lamina propria increases. the use of a diode laser in chronic parodontitis has an effect on the increase in the number of macrophages and gingival mast cells, but not on the degranulation process of mast cells.

The PPARα Regulation of the Gut Physiology in Regard to Interaction with Microbiota, Intestinal Immunity, Metabolism, and Permeability.

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed throughout the mammalian gut: in epithelial cells, in the villi of enterocytes and in Paneth cells of intestinal crypts, as well as in some immune cells (e.g., lamina propria macrophages, dendritic cells) of the mucosa. This review examines the reciprocal interaction between PPARα activation and intestinal microbiota. We refer to the published data confirming that microbiota products can influence PPARα signaling and, on the other hand, PPARα activation is able to affect microbiota profile, viability, and diversity. PPARα impact on the broad spectrum of events connected to metabolism, signaling (e.g., NO production), immunological tolerance to dietary antigens, immunity and permeability of the gut are also discussed. We believe that the phenomena described here play a prominent role in gut homeostasis. Therefore, in conclusion we propose future directions for research, including the application of synthetic activators and natural endogenous ligands of PPARα (i.e., endocannabinoids) as therapeutics for intestinal pathologies and systemic diseases assumed to be related to gut dysbiosis.

Characteristic submucosal alteration in biliary carcinogenesis of pancreaticobiliary maljunction with a focus on inflammasome activation.

This study investigated submucosal alterations in biliary carcinogenesis of pancreaticobiliary maljunction (PBM). Thirty-three patients with PBM (including seven with gallbladder [GB] cancer), four with neither biliary tract cancer nor PBM who underwent pancreaticoduodenectomy (controls), and seven with chronic cholecystitis without PBM were enrolled. Protein expression of α-smooth muscle actin (αSMA), CD68, and CD204 in the GB lamina propria and that of NLRP3 and caspase 1 in the GB epithelium and lamina propria were examined. Compared with the control and cholecystitis groups, αSMA expression was higher in the cancerous part (stroma) of the GB in patients with GB cancer + PBM and in the lamina propria of patients with PBM. The CD204/CD68 ratio in the lamina propria was higher in the PBM group than in the control and cholecystitis groups. NLRP3 and caspase 1 expression in both the lamina propria and epithelium was higher in the PBM than control group. In the PBM group, NLRP3- and caspase 1-positive cells in the lamina propria were located near the epithelium. Activated fibroblasts and M2 macrophages in the GB lamina propria may be associated with biliary carcinogenesis of PBM, possibly through inflammasome activation.

Echinococcus granulosus sensu stricto and antigen B may decrease inflammatory bowel disease through regulation of M1/2 polarization

BackgroundInflammatory bowel disease (IBD) is a chronic idiopathic disease characterized by inflammation-related epithelial barrier damage in the intestinal tract. Helminth infection reduces autoimmune disease symptoms through regulation of inflammatory responses based on hygiene theory. However, the underlying mechanisms remain unclear.MethodsBALB/c mice were infected with microcysts of E. granulosus sensu stricto and drank water containing 3.5% dextran sodium sulfate (DSS) at the 100th day post-infection. After 7 days of drinking DSS, the mouse body weight change and disease activity index (DAI) were recorded every day, and colon length and histological score were evaluated after sacrifice. After injection with antigen B (AgB), inducible nitric oxide synthase (iNOS) and Fizz1 expression and F4/80+CD11c+ M1 and F4/80+CD206+ M2 in the peritoneal cells and colon tissues were analysed by qPCR and flow cytometry, respectively. Gut microbiota were profiled by 16S rRNA sequencing of the mouse faecal samples. For in vitro assay, RAW264.7 macrophages were cultured in medium containing AgB before induction by lipopolysaccharide (LPS). Then, NO in the supernatant was measured, and the expression of cytokine genes associated with macrophages were determined by qRT-PCR.ResultsEchinococcus granulosus s.s. infection and AgB significantly reduced the symptoms and histological scores of IBD induced by DSS (P < 0.05). Flow cytometry showed that AgB inoculation increased F4/80+ and CD206+ in peritoneal cells. The results of qPCR showed that AgB significantly decreased iNOS and increased Fizz1 expression in the colon of mice inoculated by DSS (P < 0.05). Furthermore, AgB injection led to significant changes in the profiles of five genera (Paraprevotella, Odoribacter, Clostridium cluster XlVa, Oscillibacter, and Flavonifractor) in faecal samples. In vitro analysis showed that AgB reduced NO levels (P < 0.01), with a significant decrease in iNOS expression (P < 0.05) in RAW264.7 cells induced by LPS.ConclusionsEchinococcus granulosus infection and AgB may improve IBD conditions by inducing an M2-predominant cellular (F4/80+ CD206+) profile and decreasing type 1 macrophages (F4/80+CD11c+) in the intestinal lamina propria. In addition, AgB intervention induced changes in the microbiota condition of the gastrointestinal duct and reversed NO expression. Thus, AgB may be a drug candidate for IBD treatment.Graphical