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![Functional characterization of CD39-deficient granulocyte-macrophage colony-stimulating factor–activated monocytes (GMaM) in vitro and their migration in vivo. Bone marrow-derived control monocytes and GMaM were generated from CD39−/− and corresponding wild-type (WT) mice in vitro. (A) The influence of CD39 on GMaM functions was evaluated. The ability to adhere to plastic surfaces and phagocytosis of pHrodo particles is shown (n = 3). Reactive oxygen species (ROS) production is presented as mean fluorescent intensities of rhodamine positive cells (n = 3). To indirectly measure the production of retinoic acid (RA), aldehyde dehydrogenase (ALDH) activity was measured using Aldefluor and displayed as the percentage of Aldefluor-positive cells (n = 3). Nitric oxide (NO) production was determined in cell culture supernatants (n = 3). (B) Cytokine secretion after lipopolysaccharide (LPS) treatment was measured in cell culture supernatants using a bead-based multiplex assay (n = 6). (C) Chronic colitis was induced using DSS in CD45.1 mice. One day before starting the third dextran sulfate sodium (DSS) treatment cycle, the mice received CD45.2 control monocytes, GMaM, CD39−/− control monocytes, or CD39−/− GMaM (2 × 106/mouse). Two days after injection, lamina propria mononuclear cells from the colon were isolated, and infiltrating CD45.2 positive cells were stained and measured by flow cytometry. Shown is the gating strategy and respective bar graph (mean ± standard error of the mean [SEM]; n = 3–4). (D) Rag1−/− mice were simultaneously injected with naive WT CD4+ T cells (2 × 106/mouse) and CD39−/− GMaM or CD39−/− control monocytes (2 × 106/mouse). Spleens were removed after 7 days, and the presence of Foxp3+ CD4+ T cells was evaluated by flow cytometry. Shown is the mean ± SEM of total regulatory T-cells based on the number of total splenocytes. Statistical significance was determined by one-way analysis of variance with Bonferroni correction. *P < .05; **P < .01; ***P < .001; n.s., not significant.](profile/Toni-Weinhage/publication/276074564/figure/fig8/AS:282629527097350@1444395538295/Functional-characterization-of-CD39-deficient-granulocyte-macrophage-colony-stimulating.png)
Functional characterization of CD39-deficient granulocyte-macrophage colony-stimulating factor–activated monocytes (GMaM) in vitro and their migration in vivo. Bone marrow-derived control monocytes and GMaM were generated from CD39−/− and corresponding wild-type (WT) mice in vitro. (A) The influence of CD39 on GMaM functions was evaluated. The ability to adhere to plastic surfaces and phagocytosis of pHrodo particles is shown (n = 3). Reactive oxygen species (ROS) production is presented as mean fluorescent intensities of rhodamine positive cells (n = 3). To indirectly measure the production of retinoic acid (RA), aldehyde dehydrogenase (ALDH) activity was measured using Aldefluor and displayed as the percentage of Aldefluor-positive cells (n = 3). Nitric oxide (NO) production was determined in cell culture supernatants (n = 3). (B) Cytokine secretion after lipopolysaccharide (LPS) treatment was measured in cell culture supernatants using a bead-based multiplex assay (n = 6). (C) Chronic colitis was induced using DSS in CD45.1 mice. One day before starting the third dextran sulfate sodium (DSS) treatment cycle, the mice received CD45.2 control monocytes, GMaM, CD39−/− control monocytes, or CD39−/− GMaM (2 × 106/mouse). Two days after injection, lamina propria mononuclear cells from the colon were isolated, and infiltrating CD45.2 positive cells were stained and measured by flow cytometry. Shown is the gating strategy and respective bar graph (mean ± standard error of the mean [SEM]; n = 3–4). (D) Rag1−/− mice were simultaneously injected with naive WT CD4+ T cells (2 × 106/mouse) and CD39−/− GMaM or CD39−/− control monocytes (2 × 106/mouse). Spleens were removed after 7 days, and the presence of Foxp3+ CD4+ T cells was evaluated by flow cytometry. Shown is the mean ± SEM of total regulatory T-cells based on the number of total splenocytes. Statistical significance was determined by one-way analysis of variance with Bonferroni correction. *P < .05; **P < .01; ***P < .001; n.s., not significant.
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Background & Aims
Granulocyte macrophage colony-stimulating factor (GM-CSF) treatment induces clinical response in patients with active Crohn’s disease. To explore whether monocytes mediate GM-CSF effects in vivo, we used a mouse model of chronic colitis induced by dextran sulfate sodium (DSS).
Methods
Murine bone marrow-derived monocytes were act...
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Inflammatory bowel disease (IBD), particularly Crohn’s disease, frequently causes intestinal fibrosis that ultimately leads to formation of strictures requiring bowel resection. Currently there is no effective antifibrotic therapy available for this disease. Pirfenidone is a small compound that has a broad spectrum of antifibrogenic effect and has...
Citations
... About 60% of all leukocytes in the bloodstream are neutrophils, which play a significant role in type 1 and type 3 immunological responses but have a controversial role in type 2 immunity. 40,41 Severe allergies, autoimmune and autoinflammatory diseases are influenced by neutrophil dysregulation. 42 Furthermore, in FPIES, positive responses to the OFC are usually followed by a rise in the ANC of more than 3500 cells/mm3. ...
Background
Cow’s Milk Allergy (CMA) diagnosis is often a challenge due to the non-specific nature of symptoms and lack of a confirmatory diagnostic test. To our knowledge no previous studies investigated serum Eosinophil-Derived Neurotoxin (sEDN) in CMA. So, we aimed to assess the role of sEDN in CMA diagnosis.
Methods
Forty-five infants with CMA were compared to 45 infants with functional gastrointestinal disorders (FGIDs) and 45 healthy controls. For all participants, Cow’s Milk-related Symptom Score (CoMiSS) was documented, and sEDN level with hematological parameters were measured before starting elimination diet.
Results
Receiver operation characteristic (ROC) curve identified sEDN > 14 ng/mL and CoMiSS > 9 as the optimal cut-off points to discriminate CMA from other groups with sensitivity 86.67%, 97.78% and specificity 60.00%, 78.89% respectively. Additionally, absolute neutrophil count (ANC) showed the highest sensitivity and specificity (80.0% and 78.89%) among hematological parameters. Although CoMiSS and ANC showed a significant positive correlation with sEDN in CMA group, CoMiSS was the only significant predictor for sEDN in multivariate linear regression.
Conclusions
sEDN showed high sensitivity in discriminating infants with and without CMA. Therefore, it is suggested as a potential biomarker for CMA diagnosis. Also, ANC should be closely monitored in these infants.
Impact
CMA presents with high heterogeneity, which complicates the diagnosis especially non-IgE-mediated and mixed types. So, oral food challenge continues to be the gold standard for its diagnosis.
ROC curve identified CoMiSS > 9 as the best cut-off point to identify CMA. However, CoMiSS is a good awareness tool for CMA but not a diagnostic tool.
sEDN level was significantly higher in infants with CMA with a good diagnostic performance in differentiating them than those without CMA. So, it is suggested as a potential biomarker for CMA diagnosis.
ANC could have a role in CMA diagnosis and differentiating it from FGIDs.
... In addition to the gut microbiota, A2AR is also involved in maintaining intestinal homeostasis (Sun et al., 2021). Studies have indicated high expression of CD39 and CD73 in immune cells within the intestine, closely related to the intestinal lumen environment (Weinhage et al., 2015;Zhu et al., 2021). Moreover, acute Toxoplasma gondii infection leads to a marked decrease in CD73 expression and adenosine content in the intestinal lumen, resulting in intestinal mucosal injury and exacerbation of hepatic damage, whereas activation of adenosine A2AR significantly ameliorates intestinal mucosal injury (Francois et al., 2015). ...
Background
Alcoholic liver disease (ALD) is exacerbated by disruptions in intestinal microecology and immune imbalances within the gut–liver axis. The present study assesses the therapeutic potential of combining Akkermansia muciniphila (A. muciniphila) with inosine in alleviating alcohol-induced liver injury.
Methods
Male C57BL/6 mice, subjected to a Lieber-DeCarli diet with 5% alcohol for 4 weeks, served as the alcoholic liver injury model. Various analyzes, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), ELISA, immunochemistry, 16S rRNA gene sequencing, and flow cytometry, were employed to evaluate liver injury parameters, intestinal barrier function, microbiota composition, and immune responses.
Results
Compared to the model group, the A. muciniphila and inosine groups exhibited significantly decreased alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide (LPS) levels, reduced hepatic fat deposition and neutrophil infiltration, alleviated oxidative stress and inflammation, and increased expression of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1). These effects were further pronounced in the A. muciniphila and inosine combination group compared to individual treatments. While alcohol feeding induced intestinal dysbiosis and gut barrier disruption, the combined treatment reduced the abundance of harmful bacteria (Oscillibacter, Escherichia/Shigella, and Alistipes) induced by alcohol consumption, promoting the growth of butyrate-producing bacteria (Akkermansia, Lactobacillus, and Clostridium IV). Flow cytometry revealed that alcohol consumption reduced T regulatory (Treg) populations while increasing those of T-helper (Th) 1 and Th17, which were restored by A. muciniphila combined with inosine treatment. Moreover, A. muciniphila and inosine combination increased the expression levels of intestinal CD39, CD73, and adenosine A2A receptor (A2AR) along with enhanced proportions of CD4⁺CD39⁺Treg and CD4⁺CD73⁺Treg cells in the liver and spleen. The A2AR antagonist KW6002, blocked the beneficial effects of the A. muciniphila and inosine combination on liver injury in ALD mice.
Conclusion
This study reveals that the combination of A. muciniphila and inosine holds promise for ameliorating ALD by enhancing the gut ecosystem, improving intestinal barrier function, upregulating A2AR, CD73, and CD39 expression, modulating Treg cells functionality, and regulating the imbalance of Treg/Th17/Th1 cells, and these beneficial effects are partly A2AR-dependent.
... Although one cannot rule out an activated innate immune system, given the interplay and potential other sources of many of these cytokines. For example, GM-CSF activated monocytes have been shown to interact with T cells in the context of colitis [31]. It is noteworthy that the adoptive T cell transfer model not only had more statistically relevant inflammatory markers, but also higher concentrations of all markers tested ( Figures 4B and 5). ...
Inflammatory bowel disease (IBD) is a chronic ailment afflicting millions of people worldwide, with the majority of recognized cases within industrialized countries. The impacts of IBD at the individual level are long-lasting with few effective treatments available, resulting in a large burden on the health care system. A number of existing animal models are utilized to evaluate novel treatment strategies. Two commonly used models are (1) acute colitis mediated by dextran sulphate sodium (DSS) treatment of wild-type mice and (2) chronic colitis mediated by the transfer of proinflammatory T cells into immunodeficient mice. Despite the wide use of these particular systems to evaluate IBD therapeutics, the typical readouts of clinical disease progression vary depending on the model used, which may be reflective of mechanistic differences of disease induction. The most reliable indicator of disease in both models remains intestinal damage which is typically evaluated upon experimental endpoint. Herein, we evaluated the expression profile of a panel of cytokines and chemokines in both DSS and T cell transfer models in an effort to identify a number of inflammatory markers in the blood that could serve as reliable indicators of the relative disease state. Out of the panel of 25 markers tested, 6 showed statistically significant shifts with the DSS model, compared to 11 in the T cell transfer model with IL-6, IL-13, IL-22, TNF-α and IFN-γ being common markers of disease in both models. Our data highlights biological differences between animal models of IBD and helps to guide future studies when selecting efficacy readouts during the evaluation of experimental IBD therapeutics.
... Monocytes and macrophages also play an important role in maintaining intestinal homeostasis by clearing bacterial antigens and apoptotic cells and enhancing or inhibiting the action of other immune cells, depending on the prevailing microenvironment. Due to their migratory capacity and specific mode of action, monocytes are of increasing interest for use as cellular therapeutics for inflammation-related diseases and cancer [3][4][5][6][7][8]. The possibility of using ex vivo modified monocytes to treat arteriogenesis was already investigated in 2006 by Herold et al. [3]; however, this group also pointed out problems with isolation and the culture of these cells. ...
Background:
Monocyte-derived macrophages or dendritic cells are of increasing interest for cellular therapeutic products to treat inflammation-related diseases and cancer. However, the isolation method and the culture conditions applied influence the functionality of cells. For some approaches, the adhesion-induced differentiation into macrophages must be prevented to maintain functions attributed to circulating monocytes. The effects of the isolation method on the functionality of non-adherent peripheral monocytes have not yet been investigated.
Methods:
The present study examines the impact of the isolation method on cell viability, growth, metabolism, inflammation-induced cytokine response, migratory capacity, and adherence of non-adherent human peripheral monocytes. The monocytes were isolated by magnetic sorting using either positive or negative selection and cultured in cell-repellent plates.
Results:
The purity and yield of monocytes were higher after positive selection. However, the adherence and migratory capacity, cytokine response, and metabolic activity were decreased compared to negatively selected monocytes. The impaired functionality presented in combination with cell shrinking, thus, indicates the start of cell viability loss. Negatively selected non-adherent monocytes showed no impairment in functionality, and the viability remained high. In conclusion, this approach is better suited for conducting ex vivo modifications of monocytes prior to the intended experimental setup or therapeutic application.
... GM-CSF in particular plays an integral role in intestinal innate immunity, immune tolerance and the induction of intestinal regulatory T cells (12,13). Pediatric and adult CD patients with ileal and stricturing or penetrating disease were shown to have higher levels of GM-CSF autoantibodies (14). ...
Background: TNF-α has a major role in the pathogenesis of Crohn's disease (CD). In contrast, GM-CSF may be beneficial for its anti-inflammatory role in a subset of patients with CD with antibodies against GM-CSF as seen in prior trials of GM-CSF which resulted in clinical improvement in CD. We developed butanol purified Food Allergy Herbal Formula-2 (B-FAHF-2) by refining FAHF-2. FAHF-2 suppressed TNF-α production by human peripheral blood mononuclear cells (PBMCs) and colonic mucosa, and abrogated colitis in a murine model. We sought to examine the effect of B-FAHF-2 and the herbs that comprise it on TNF-α and GM-CSF production as a potential herbal therapy for the treatment of CD.
Methods: B-FAHF-2 was examined using high pressure liquid chromatography (HPLC) and compared to the original formulation, FAHF-2. PBMCs from pediatric patients with CD were cultured with lipopolysaccharide and B-FAHF-2, individual herbs or medium alone. Colonic biopsy specimens were cultured with or without B-FAHF-2. TNF-α and GM-CSF were measured by enzyme-linked immunosorbent assay (ELISA). B-FAHF-2 efficacy was tested in vivo in the CD45Rb hi transfer model.
Results: B-FAHF-2 had a similar HPLC fingerprint as FAHF-2 but decreased TNF-α production by PBMCs and colonic mucosa from pediatric CD subjects at 20% of the FAHF-2 dose. B-FAHF-2 increased GM-CSF production by PBMCs and colonic mucosa from pediatric CD subjects including those with antibodies to GM-CSF. Of B-FAHF-2's herbal constituents, only Huang Bai suppressed TNF-α and increased GM-CSF production. In the murine model, B-FAHF-2 treatment alleviated colitis.
Conclusions: B-FAHF-2 decreased TNF-α production by PBMCs and colonic mucosa from pediatric subjects at a lower dose than FAHF-2. B-FAHF-2 also increased GM-CSF production by PBMCs independent of antibodies. B-FAHF-2 may have a benefit in CD patients.
... The intermediate monocyte population comprises 2-8% of circulating monocytes and includes functions such as the production of reactive oxygen species, antigen presentation, T cell stimulation, and inflammatory responses. According to their migratory ability and specific mode of action, classical monocytes are of rising interest for their application as cellular-based therapeutic products to treat inflammation-related diseases or cancer [6][7][8][9][10][11]. The underlying mechanism of action is that the injected genetically or biochemically modified monocytes are recruited to the site of inflammation, followed by migration into inflamed tissue and exerting their intended therapeutic effect. ...
Ex vivo culture conditions during the manufacturing process impact the therapeutic effect of cell-based products. Mimicking blood flow during ex vivo culture of monocytes has beneficial effects by preserving their migratory ability. However, the effects of shear flow on the inflammatory response have not been studied so far. Hence, the present study investigates the effects of shear flow on both blood-derived naïve and activated monocytes. The activation of monocytes was experimentally induced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which acts as a pro-survival and growth factor on monocytes with a potential role in inflammation. Monocytes were cultured under dynamic (=shear flow) or static conditions while preventing monocytes' adherence by using cell-repellent surfaces to avoid adhesion-induced differentiation. After cultivation (40 h), cell size, viability, and cytokine secretion were evaluated, and the cells were further applied to functional tests on their migratory capacity, adherence, and metabolic activity. Our results demonstrate that the application of shear flow resulted in a decreased pro-inflammatory signaling concurrent with increased secretion of the anti-inflammatory cytokine IL-10 and increased migratory capacity. These features may improve the efficacy of monocyte-based therapeutic products as both the unwanted inflammatory signaling in blood circulation and the loss of migratory ability will be prevented.
... Resident macrophages produce anti-inflammatory cytokines, such as IL-10 and TGF-β. Studies have reported that IL-10 produced by macrophages has the effect of regulating the expression of Foxp3 + Tregs, and macrophages highly express the TGF-β receptor and participate in the signal transduction of activated TGF-β (Figure 2; Mowat and Bain, 2011;Weinhage et al., 2015). TGF-β can combine with the Foxp3 expressed by Tregs to form CD4 + Foxp3 + Tregs, which can reduce the activation of macrophages and translocation of NF-κB in the mucosa . ...
Macrophages, which are functional plasticity cells, have the ability to phagocytize and digest foreign substances and acquire pro-(M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. The large number of macrophages in the intestinal tract, play a significant role in maintaining the homeostasis of microorganisms on the surface of the intestinal mucosa and in the continuous renewal of intestinal epithelial cells. They are not only responsible for innate immunity, but also participate in the development of intestinal inflammation. A clear understanding of the function of macrophages, as well as their role in pathogens and inflammatory response, will delineate the next steps in the treatment of intestinal inflammatory diseases. In this review, we discuss the origin and development of macrophages and their role in the intestinal inflammatory response or infection. In addition, the effects of macrophages in the occurrence and development of inflammatory bowel disease (IBD), and their role in inducing fibrosis, activating T cells, reducing colitis, and treating intestinal inflammation were also reviewed in this paper.
... In chronic DSS-induced colitis, adoptive transfer of GM-CSF activated monocytes (GMaM) leads to substantial clinical improvement, as demonstrated by reduction of weight loss, inflammatory infiltration, ulceration, and colon shrinkage. Compared with control monocytes, GMaM express higher levels of NTPDase1/CD39 and NT5E/CD73, migrate faster and persist longer in the inflamed intestine, thus inducing a more efficient Treg cells generation (Weinhage et al., 2015). While NTPDase1/CD39 expression on Treg cells behaves as a heritable trait shaping adaptive immune response (Roederer et al., 2015), altered Treg NT5E/CD73 expression seems to be more extensively affected by environmental factors such as pathogens, diet or microbiome components (Mangino et al., 2017). ...
Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP, AMP and NAD⁺. Ectonucleotidases, expressed by virtually all cell types, immune cells included, either as plasma membrane-associated or secreted enzymes, are classified into four main families: 1) nucleoside triphosphate diphosphohydrolases (NTPDases), 2) nicotinamide adenine dinucleotide glycohydrolase (NAD glycohydrolase/ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1), 3) ecto-5′-nucleotidase (NT5E), and 4) ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). Concentration of ATP, UTP and NAD⁺ can be increased in the extracellular space thanks to un-regulated, e.g., cell damage or cell death, or regulated processes. Regulated processes include secretory exocytosis, connexin or pannexin hemichannels, ATP binding cassette (ABC) transporters, calcium homeostasis modulator (CALMH) channels, the ATP-gated P2X7 receptor, maxi-anion channels (MACs) and volume regulated ion channels (VRACs). Hydrolysis of extracellular purine nucleotides generates adenosine, an important immunosuppressant. Extracellular nucleotides and nucleosides initiate or dampen inflammation via P2 and P1 receptors, respectively. All these agents, depending on their level of expression or activation and on the agonist concentration, are potent modulators of inflammation and key promoters of host defences, immune cells activation, pathogen clearance, tissue repair and regeneration. Thus, their knowledge is of great importance for a full understanding of the pathophysiology of acute and chronic inflammatory diseases. A selection of these pathologies will be briefly discussed here.
... 52 Furthermore, systemic STAT3 hyperactivation ameliorated experimental colitis, whereas STAT3 deficiency of myeloid cells led to severe murine colitis with increase of pro-inflammatory cytokines like IFN-γ and inhibition of regulatory IL-10, 53 which is accordance with our data in terms of lower IL-10 levels, higher proinflammatory IL-23 levels upon IFN-γ in UC monocytes, and missing IFN-γ-dependent STAT3 activation in UC. Adjacently, the regulatory surface marker CD39, which is involved in regulatory T cell induction 38 and is most likely regulated via STAT3 in monocytes/macrophages, 40,41 was also significantly weakly expressed in UC monocytes in line with their missing IFN-γdependent STAT3 activation, whereas CD and control monocytes showed a higher CD39 expression in accordance with their intact STAT3 axis. According to these data, a rather protective role of STAT3 in IEC and monocytes/macrophages is suggested, and increased levels of activated STAT3 may be an attempt to stabilize intestinal barrier function in IBD. ...
Background
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor tofacitinib has been recently approved for the treatment of ulcerative colitis (UC) but not Crohn’s disease (CD). Systematic analysis of the JAK/STAT pathway in inflammatory bowel disease is still missing. The aim of this study was to investigate JAK/STAT activation and adjacent signaling in monocytes of patients with inflammatory bowel diseases, which are key players in inflammatory responses.
Methods
Blood samples of active UC (n = 28) and CD patients (n = 28) and healthy controls (n = 22) were collected for primary monocyte investigation. STAT phosphorylation (pSTAT), cytokine secretion, and surface marker expression ± prior tofacitinib blockade in addition to Th-17 and regulatory T cell induction in cocultures were analyzed upon interferon (IFN)-γ timulation.
Results
Baseline frequencies of pSTAT1+ and pSTAT3+ monocytes were significantly higher in UC, whereas IFN-γ-associated crosstalk induction of pSTAT3+ monocytes was missing in UC-derived monocytes compared with controls and CD. This coincided with decreased interleukin (IL)-10 and cluster of differentiation (CD)39 levels, diminished regulatory T cell (Treg) induction, and increased IL-12 and IL-23 secretion compared with controls, which was not observed in CD monocytes. Tofacitinib induced stronger inhibition of inflammatory cytokine release (IL-6, TNFα, IL-12, IL-23) in UC compared with CD monocytes.
Conclusions
In UC monocytes, IFN-γ-associated activation of the JAK/STAT pathway is impaired with an imbalance between STAT1 and STAT3, coinciding with stronger induction of inflammatory monocytes by IFN-γ compared with controls or CD. The fact that tofacitinib had stronger regulatory impact on UC than on CD monocytes further underlines a stronger inflammatory involvement of the JAK/STAT pathway in UC pathogenesis, which might result from missing STAT3 activation to counteract STAT1-induced inflammation.
... In contrast, a more favorable course of TNBS-induced colitis has been observed in CD39-null mice when compared to wild type controls (39). In the context of DSS colitis, ENTPD1/CD39 and CD73 expression on activated macrophages was found to limit inflammation, either by directly hydrolyzing pro-inflammatory extracellular ATP into adenosine or by indirectly promoting Treg development (40). Further, in the same experimental model, CD39 deletion exacerbated colitis as reflected by heightened disease activity index, higher levels of pro-inflammatory markers and histological evidence of tissue injury. ...
Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.
