scholarly journals Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells

2014 ◽  
Vol 307 (3) ◽  
pp. G338-G346 ◽  
Author(s):  
Courtney C. Kurtz ◽  
Ioannis Drygiannakis ◽  
Makoto Naganuma ◽  
Sanford Feldman ◽  
Vasileios Bekiaris ◽  
...  
Keyword(s):  
Adoptive Transfer ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
T Cell Subsets ◽  
Transfer Model ◽  
Wild Type ◽  
Colonic Inflammation ◽  
Th Cells ◽  
Extracellular Adenosine

Adenosine is a purine metabolite that can mediate anti-inflammatory responses in the digestive tract through the A2A adenosine receptor (A2AAR). We examined the role of this receptor in the control of inflammation in the adoptive transfer model of colitis. Infection of A2AAR−/− mice with Helicobacter hepaticus increased colonic inflammation scores compared with uninfected A2AAR controls. Comparison of T cell subsets in wild-type and A2AAR−/− mice revealed differences in markers associated with activated helper T (Th) cells and regulatory T (Treg) cells. Previous studies showed that expression of A2AAR on CD45RBHI and CD45RBLO Th cells is essential for the proper regulation of colonic inflammation. Adoptive transfer of CD45RBHI with CD45RBLO from wild-type mice into RAG1−/−/A2AAR−/− mice induced severe disease within 3 wk, although transfer of the same subsets into RAG1−/− mice does not induce colitis. This suggests that the presence of A2AAR on recipient cells is also important for controlling colitis. To investigate the role of A2AAR in myeloid cells, chimeric recipients were generated by injection of bone marrow from RAG1−/− or RAG1−/−/A2AAR−/− mice into irradiated RAG1−/− mice. After adoptive transfer, these recipients did not develop colitis, regardless of A2AAR expression by the donor. Together, our results suggest that the control of inflammation in vivo is dependent on A2AAR signaling through multiple cell types that collaborate in the regulation of colitis by responding to extracellular adenosine.

Gastrointestinal Chlamydia -induced CD8 + T cells promote chlamydial pathogenicity in the female upper genital tract

2021 ◽  
Author(s):  
Qi Tian ◽  
Zengzi Zhou ◽  
Luying Wang ◽  
Xin Sun ◽  
Bernard Arulanandam ◽  
...  
Keyword(s):  
T Cells ◽  
Gastrointestinal Tract ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Genital Tract ◽  
Wild Type ◽  
Necessary And Sufficient ◽  
Lymphocyte Responses

Chlamydia is known to both ascend to the upper genital tract and spread to the gastrointestinal tract following intravaginal inoculation. The gastrointestinal Chlamydia was recently reported to promote chlamydial pathogenicity in the genital tract since mice intravaginally inoculated with an attenuated Chlamydia , which alone failed to develop pathology in the genital tract, were restored to develop hydrosalpinx by intragastric co-inoculation with wild type Chlamydia . Gastrointestinal Chlamydia promoted hydrosalpinx via an indirect mechanism since Chlamydia in the gut did not directly spread to the genital tract lumen. In the current study, we further investigated the role of CD8 + T cells in the promotion of hydrosalpinx by gastrointestinal Chlamydia . First, we confirmed that intragastric co-inoculation with wild type Chlamydia promoted hydrosalpinx in mice that were inoculated with an attenuated Chlamydia in the genital tract one week earlier. Second, the promotion of hydrosalpinx by intragastrically co-inoculated Chlamydia was blocked by depleting CD8 + T cells. Third, adoptive transfer of the gastrointestinal Chlamydia -induced CD8 + T cells was sufficient for promoting hydrosalpinx in mice that were intravaginally inoculated with an attenuated Chlamydia . These observations have demonstrated that CD8 + T cells induced by gastrointestinal Chlamydia are both necessary and sufficient for promoting hydrosalpinx in the genital tract. The study has laid a foundation for further revealing the mechanisms by which Chlamydia -induced T lymphocyte responses (as a 2 nd hit) promote hydrosalpinx in mice with genital Chlamydia -triggered tubal injury (as a 1 st hit), a continuing effort in testing the two-hit hypothesis as a chlamydial pathogenic mechanism.

scholarly journals GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Taeyeop Park ◽  
Huazhen Chen ◽  
Hee-Yong Kim
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Cytokine Expression ◽  
Regulatory Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Condition ◽  
Wild Type ◽  
Knock Out ◽  
The Brain

Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.

scholarly journals Toll-Like Receptor 9 Modulates Immune Responses to Aspergillus fumigatus Conidia in Immunodeficient and Allergic Mice

2008 ◽  
Vol 77 (1) ◽  
pp. 108-119 ◽  
Author(s):  
Hemanth Ramaprakash ◽  
Toshihiro Ito ◽  
Theodore J. Standiford ◽  
Steven L. Kunkel ◽  
Cory M. Hogaboam
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Inflammatory Responses ◽  
Fungal Growth ◽  
Lower Airway ◽  
Interleukin 17 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Immunodeficient Mice

ABSTRACT The role of Toll-like receptor 9 (TLR9) in antifungal responses in the immunodeficient and allergic host is unclear. We investigated the role of TLR9 in murine models of invasive aspergillosis and fungal asthma. Neutrophil-depleted TLR9 wild-type (TLR9+/+) and TLR9-deficient (TLR9−/−) mice were challenged with resting or swollen Aspergillus fumigatus conidia and monitored for survival and lung inflammatory responses. The absence of TLR9 delayed, but did not prevent, mortality in immunodeficient mice challenged with resting or swollen conidia compared to TLR9+/+ mice. In a fungal asthma model, TLR9+/+ and TLR9−/− mice were sensitized to soluble A. fumigatus antigens and challenged with resting or swollen A. fumigatus conidia, and both groups of mice were analyzed prior to and at days 7, 14, and 28 after the conidium challenge. When challenged with resting conidia, TLR9−/− mice exhibited significantly lower airway hyper-responsiveness compared to the TLR9+/+ groups. In contrast, A. fumigatus-sensitized TLR9−/− mice exhibited pulmonary fungal growth at days 14 and 28 after challenge with swollen conidia, a finding never observed in their allergic wild-type counterparts. Increased fungal growth in allergic TLR9−/− mice correlated with markedly decreased dectin-1 expression in whole lung samples and isolated dendritic cell populations. Further, whole lung levels of interleukin-17 were lower in allergic TLR9−/− mice compared to similar TLR9+/+ mice. Together, these data suggest that TLR9 modulates pulmonary antifungal immune responses to swollen conidia, possibly through the regulation of dectin-1 expression.

scholarly journals Interleukin-10 Negatively Regulates Local Cytokine and Chemokine Production but Does Not Influence Antibacterial Host Defense during Murine Pneumococcal Meningitis

2003 ◽  
Vol 71 (4) ◽  
pp. 2276-2279 ◽  
Author(s):  
Petra J. G. Zwijnenburg ◽  
Tom van der Poll ◽  
Sandrine Florquin ◽  
John J. Roord ◽  
A. Marceline van Furth
Keyword(s):  
Host Defense ◽  
Pneumococcal Meningitis ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Wild Type ◽  
Chemokine Production ◽  
Local Host ◽  
Antibacterial Host Defense ◽  
Local Cytokine

ABSTRACT To determine the role of endogenous interleukin-10 (IL-10) in local host defense during pneumococcal meningitis, the inflammatory responses of IL-10-gene-deficient and wild-type mice after the induction of meningitis were compared. The absence of IL-10 was associated with higher cytokine and chemokine concentrations and a more pronounced infiltrate, but antibacterial defense or survival was not influenced.

scholarly journals Pseudomonas aeruginosa Keratitis in Knockout Mice Deficient in Intercellular Adhesion Molecule 1

1999 ◽  
Vol 67 (2) ◽  
pp. 972-975 ◽  
Author(s):  
Jeffery A. Hobden ◽  
Sharon Masinick-McClellan ◽  
Ronald P. Barrett ◽  
Kenneth S. Bark ◽  
Linda D. Hazlett
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Adhesion Molecule ◽  
Knockout Mice ◽  
Severe Disease ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Disease Response

ABSTRACT In this study, the role of intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of Pseudomonas aeruginosakeratitis was examined by using inbred ICAM-1-deficient knockout mice. These mice had significantly less (P ≤ 0.02) ocular disease than wild-type mice, suggesting that ICAM-1 contributes to a more severe disease response following P. aeruginosainfection.

scholarly journals Unraveling the role of B cells in the pathogenesis of an oncogenic avian herpesvirus

2018 ◽  
Vol 115 (45) ◽  
pp. 11603-11607 ◽  
Author(s):  
Luca D. Bertzbach ◽  
Maria Laparidou ◽  
Sonja Härtle ◽  
Robert J. Etches ◽  
Bernd Kaspers ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Reverse Genetics ◽  
Gene Segment ◽  
T Cell Subsets ◽  
Bursa Of Fabricius ◽  
Wild Type ◽  
Ig Heavy Chain ◽  
Peripheral B Cells

Marek’s disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes immunosuppression, paralysis, and deadly lymphomas in chickens. In infected animals, B cells are efficiently infected and are thought to amplify the virus and transfer it to T cells. MDV subsequently establishes latency in T cells and transforms CD4+T cells, resulting in fatal lymphomas. Despite many years of research, the exact role of the different B and T cell subsets in MDV pathogenesis remains poorly understood, mostly due to the lack of reverse genetics in chickens. Recently, Ig heavy chain J gene segment knockout (JH-KO) chickens lacking mature and peripheral B cells have been generated. To determine the role of these B cells in MDV pathogenesis, we infected JH-KO chickens with the very virulent MDV RB1B strain. Surprisingly, viral load in the blood of infected animals was not altered in the absence of B cells. More importantly, disease and tumor incidence in JH-KO chickens was comparable to wild-type animals, suggesting that both mature and peripheral B cells are dispensable for MDV pathogenesis. Intriguingly, MDV efficiently replicated in the bursa of Fabricius in JH-KO animals, while spread of the virus to the spleen and thymus was delayed. In the absence of B cells, MDV readily infected CD4+and CD8+T cells, allowing efficient virus replication in the lymphoid organs and transformation of T cells. Taken together, our data change the dogma of the central role of B cells, and thereby provide important insights into MDV pathogenesis.

Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3455-3464 ◽  
Author(s):  
Richard A. Dean ◽  
Jennifer H. Cox ◽  
Caroline L. Bellac ◽  
Alain Doucet ◽  
Amanda E. Starr ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Binding Motif ◽  
Wild Type ◽  
Lps Challenge ◽  
Inflammatory Protein ◽  
Leukocyte Influx ◽  
Cc Chemokines ◽  
Intranasal Instillation

AbstractThrough the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)—thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR+ CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, -2, and -3 at E-LR. MMP-12-cleaved mCXCL2 (macrophage-inflammatory protein-2 [MIP-2]) and mCXCL3 (dendritic cell inflammatory protein-1 [DCIP-1]) lost chemotactic activity. Furthermore, MMP-12 processed and inactivated monocyte chemotactic proteins CCL2, -7, -8, and -13 at position 4-5 generating CCR antagonists. Indeed, PMNs and macrophages in bronchoalveolar lavage fluid were significantly increased 72 hours after intranasal instillation of LPS in Mmp12−/− mice compared with wild type. Specificity occurred at 2 levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR+CXC chemokines, mCXCL5 (LPS-induced CXC chemokine [LIX]) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine, promoting enhanced PMN early infiltration in wild-type mice compared with Mmp12−/− mice 8 hours after LPS challenge in air pouches. We propose that the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR+CXC and CC chemokines.

scholarly journals The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules [corrected]

1993 ◽  
Vol 178 (5) ◽  
pp. 1837-1842 ◽  
Author(s):  
J M Penninger ◽  
N Neu ◽  
E Timms ◽  
V A Wallace ◽  
D R Koh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Severe Disease ◽  
Heart Tissue ◽  
T Cell Subsets ◽  
Autoimmune Myocarditis ◽  
Cd8 Cells ◽  
Organ Specific

Experimental induction of most autoimmune diseases appears to depend on the activation of CD4+ T helper cells, while CD8+ lymphocytes may have a role in disease progression. To study the role of CD4+ and CD8+ T cell subsets in T cell-dependent autoimmunity, mice lacking CD4 or CD8 molecules after gene targeting were injected with cardiac myosin to induce organ specific autoimmune myocarditis. Mice homozygous for the CD8 mutation (CD8-/-) developed significantly more severe disease as compared to CD4+/-CD8+/- controls. Surprisingly, CD4-/- mice developed autoimmune myocarditis with infiltration of TCR alpha beta +CD4-CD8- T cells in the heart tissue and appearance of autoantibodies. These data demonstrate that the lack of CD4+ or CD8+ T cells has no significant influence on the initiation of autoimmune myocarditis. CD4+ and CD8+ cells regulate disease severity and these results may explain the occurrence of autoimmunity in CD4 immunodeficiencies.

scholarly journals CD73 Is Critical for the Resolution of Murine Colonic Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Margaret S. Bynoe ◽  
Adam T. Waickman ◽  
Deeqa A. Mahamed ◽  
Cynthia Mueller ◽  
Jeffrey H. Mills ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dextran Sulfate ◽  
Adenosine Monophosphate ◽  
Negative Regulator ◽  
Cellular Damage ◽  
Wild Type ◽  
Extracellular Adenosine ◽  
Glycosyl Phosphatidylinositol ◽  
Cd73 Expression

CD73 is a glycosyl-phosphatidylinositol-(GPI-) linked membrane protein that catalyzes the extracellular dephosphorylation of adenosine monophosphate (AMP) to adenosine. Adenosine is a negative regulator of inflammation and prevents excessive cellular damage. We investigated the role of extracellular adenosine in the intestinal mucosa during the development of Dextran-Sulfate-Sodium-(DSS-)salt-induced colitis in mice that lack CD73 (CD73−/−) and are unable to synthesize extracellular adenosine. We have found that, compared to wild-type (WT) mice, CD73−/−mice are highly susceptible to DSS-induced colitis. CD73−/−mice exhibit pronounced weight loss, slower weight recovery, an increase in gut permeability, a decrease in expression of tight junctional adhesion molecules, as well as unresolved inflammation following the removal of DSS. Moreover, colonic epithelia in CD73−/−mice exhibited increased TLR9 expression, high levels of IL-1βand TNF-α, and constitutive activation of NF-κB. We conclude that CD73 expression in the colon is critical for regulating the magnitude and the resolution of colonic immune responses.

scholarly journals Improved exercise anaerobic power and less central fatigue in CD73 knockout mice

2021 ◽  
Author(s):  
Aderbal S Aguiar ◽  
Ana Elisa Speck ◽  
Paula M. Canas ◽  
Rodrigo A. Cunha
Keyword(s):  
Physical Performance ◽  
Effect Size ◽  
Respiratory Exchange Ratio ◽  
Anaerobic Power ◽  
Central Fatigue ◽  
Wild Type ◽  
Extracellular Adenosine ◽  
Small Effect Size ◽  
Ergogenic Effects

ABSTRACTEcto-5′-nucleotidase CD73 is the main source of extracellular adenosine involved in the activation of adenosine A2A receptors responsible for the ergogenic effects of caffeine. We now investigated the role of CD73 in exercise by comparing female wild-type (WT) and CD73 knockout (KO) mice in a treadmill graded test to evaluate running power, oxygen uptake , and respiratory exchange ratio (RER) – the gold standards characterizing physical performance. Spontaneous locomotion in the open field and submaximal exercise performance in the treadmill were similar between CD73-KO and WT mice; also demonstrated equivalent aerobic power. However, CD73-KO displayed higher anaerobic power indexes, namely a 43.7±4.2% larger critical power (large effect size, P <0.05) and 3.8±0.4 increase of maximum RER (small effect size, P <0.05). Thus, KO of CD73 was ergogenic, i.e., it increased physical performance, suggesting that CD73-mediated formation of extracellular adenosine signals fatigue.

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