scholarly journals IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+macrophage phenotype

2019 ◽  
Author(s):  
Alastair L. Corbin ◽  
Maria Gomez-Vazquez ◽  
Tariq E. Khoyratty ◽  
Dorothée L. Berthold ◽  
Hannah Almuttaqi ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interferon Regulatory Factor ◽  
Mononuclear Phagocytes ◽  
Helicobacter Hepaticus ◽  
Macrophage Phenotype ◽  
Wild Type ◽  
Regulatory Factor ◽  
Monocyte Differentiation ◽  
Inflammatory Phenotype ◽  
The Impact

AbstractMononuclear phagocytes (MNPs) play a key role in maintaining intestinal homeostasis but also in triggering immunopathology in response to acute microbial stimulation, which induces the recruitment of masses of Ly6Chimonocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon Regulatory Factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state, but ameliorates immunopathology duringHelicobacter hepaticusinduced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single cell RNA-sequencing approaches we compare the differentiation trajectories of wild type and IRF5 deficient monocytes in a shared inflammatory environment and demonstrate that IRF5 stipulates a choice in monocyte differentiation towards macrophages. Specifically, IRF5 promotes the generation of pathogenic CD11c+macrophages and controls the production of inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional controller of pathogenic monocyte differentiation in the gut.

scholarly journals IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation

2020 ◽  
Vol 5 (47) ◽  
pp. eaax6085 ◽  
Author(s):  
Alastair L. Corbin ◽  
Maria Gomez-Vazquez ◽  
Dorothée L. Berthold ◽  
Moustafa Attar ◽  
Isabelle C. Arnold ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Transcriptional Regulator ◽  
Interferon Regulatory Factor ◽  
Mononuclear Phagocytes ◽  
Helicobacter Hepaticus ◽  
Macrophage Phenotype ◽  
Regulatory Factor ◽  
Inflammatory Phenotype ◽  
The Impact

Mononuclear phagocytes (MNPs) are vital for maintaining intestinal homeostasis but, in response to acute microbial stimulation, can also trigger immunopathology, accelerating recruitment of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon regulatory factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here, we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state but ameliorates immunopathology during Helicobacter hepaticus–induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single-cell RNA-sequencing approaches, we examined the intrinsic role of IRF5 in controlling colonic MNP development. We demonstrate that IRF5 promotes differentiation of Ly6Chi monocytes into CD11c+ macrophages and controls the production of antimicrobial and inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional regulator of the colonic MNP system during intestinal inflammation.

scholarly journals Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 772
Author(s):  
Javier Conde ◽  
Marlene Schwarzfischer ◽  
Egle Katkeviciute ◽  
Janine Häfliger ◽  
Anna Niechcial ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Titanium Dioxide ◽  
Genetic Risk ◽  
Intestinal Inflammation ◽  
Sodium Sulphate ◽  
Food Additive ◽  
Wild Type ◽  
Dextran Sodium Sulphate ◽  
Risk Gene ◽  
The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

scholarly journals Role of the Helicobacter hepaticus Flagellar Sigma Factor FliA in Gene Regulation and Murine Colonization

2008 ◽  
Vol 190 (19) ◽  
pp. 6398-6408 ◽  
Author(s):  
Torsten Sterzenbach ◽  
Lucie Bartonickova ◽  
Wiebke Behrens ◽  
Birgit Brenneke ◽  
Jessika Schulze ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Sigma Factor ◽  
Intestinal Inflammation ◽  
Gall Stone ◽  
Helicobacter Hepaticus ◽  
Intestinal Colonization ◽  
Wild Type ◽  
Chronic Intestinal Inflammation ◽  
Flagellar Genes

ABSTRACT The enterohepatic Helicobacter species Helicobacter hepaticus colonizes the murine intestinal and hepatobiliary tract and is associated with chronic intestinal inflammation, gall stone formation, hepatitis, and hepatocellular carcinoma. Thus far, the role of H. hepaticus motility and flagella in intestinal colonization is unknown. In other, closely related bacteria, late flagellar genes are mainly regulated by the sigma factor FliA (σ28). We investigated the function of the H. hepaticus FliA in gene regulation, flagellar biosynthesis, motility, and murine colonization. Competitive microarray analysis of the wild type versus an isogenic fliA mutant revealed that 11 genes were significantly more highly expressed in wild-type bacteria and 2 genes were significantly more highly expressed in the fliA mutant. Most of these were flagellar genes, but four novel FliA-regulated genes of unknown function were identified. H. hepaticus possesses two identical copies of the gene encoding the FliA-dependent major flagellin subunit FlaA (open reading frames HH1364 and HH1653). We characterized the phenotypes of mutants in which fliA or one or both copies of the flaA gene were knocked out. flaA_1 flaA_2 double mutants and fliA mutants did not synthesize detectable amounts of FlaA and possessed severely truncated flagella. Also, both mutants were nonmotile and unable to colonize mice. Mutants with either flaA gene knocked out produced flagella morphologically similar to those of wild-type bacteria and expressed FlaA and FlaB. flaA_1 mutants which had flagella but displayed reduced motility did not colonize mice, indicating that motility is required for intestinal colonization by H. hepaticus and that the presence of flagella alone is not sufficient.

scholarly journals Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

2010 ◽  
Vol 84 (14) ◽  
pp. 6900-6908 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Andrea J. Pruijssers ◽  
Lianna Li ◽  
Pranav Danthi ◽  
Barbara Sherry ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Virulent Strain ◽  
Survival Rates ◽  
Adaptive Immune Response ◽  
Interferon Regulatory Factor ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Newborn Mice ◽  
Strain Type

ABSTRACT Apoptosis is a pathological hallmark of encephalitis and myocarditis caused by reovirus in newborn mice. In cell culture models, the antiviral transcription factor interferon regulatory factor 3 (IRF-3) enhances reovirus-induced apoptosis following activation via retinoic acid inducible gene I and interferon promoter-stimulating factor 1. To determine the role of IRF-3 in reovirus disease, we infected newborn IRF-3+/+ and IRF-3−/− mice perorally with mildly virulent strain type 1 Lang (T1L) and fully virulent strain type 3 SA+ (T3SA+) and monitored infected animals for survival. Both wild-type and IRF-3−/− mice succumbed with equivalent frequencies to infection with T3SA+. However, the absence of IRF-3 was associated with significantly decreased survival rates following infection with T1L. The two virus strains achieved similar peak titers in IRF-3+/+ and IRF-3−/− mice in the intestine, brain, heart, liver, and spleen. However, by day 12 postinoculation, titers in all organs examined were 10- to 100-fold higher in IRF-3−/− mice than those in wild-type mice. Increased titers were associated with marked pathological changes in all organs examined, especially in the heart, where absence of IRF-3 resulted in severe myocarditis. Cellular and humoral immune responses were equivalent in wild-type and IRF-3−/− animals, suggesting that IRF-3 functions independently of the adaptive immune response to enhance reovirus clearance. Thus, IRF-3 serves to facilitate virus clearance and prevent tissue injury in response to reovirus infection.

scholarly journals Bunyamwera Virus Nonstructural Protein NSs Counteracts Interferon Regulatory Factor 3-Mediated Induction of Early Cell Death

2003 ◽  
Vol 77 (14) ◽  
pp. 7999-8008 ◽  
Author(s):  
Alain Kohl ◽  
Reginald F. Clayton ◽  
Friedemann Weber ◽  
Anne Bridgen ◽  
Richard E. Randall ◽  
...  
Keyword(s):  
Cell Death ◽  
Defense Mechanism ◽  
Nonstructural Protein ◽  
Interferon Regulatory Factor ◽  
Wild Type Virus ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Viral Spread ◽  
Bunyamwera Virus

ABSTRACT The genome of Bunyamwera virus (BUN; family Bunyaviridae, genus Orthobunyavirus) consists of three segments of negative-sense RNA. The smallest segment, S, encodes two proteins, the nonstructural protein NSs, which is nonessential for viral replication and transcription, and the nucleocapsid protein N. Although a precise role in the replication cycle has yet to be attributed to NSs, it has been shown that NSs inhibits the induction of alpha/beta interferon, suggesting that it plays a part in counteracting the host antiviral defense. A defense mechanism to limit viral spread is programmed cell death by apoptosis. Here we show that a recombinant BUN that does not express NSs (BUNdelNSs) induces apoptotic cell death more rapidly than wild-type virus. Screening for apoptosis pathways revealed that the proapoptotic transcription factor interferon regulatory factor 3 (IRF-3) was activated by both wild-type BUN and BUNdelNSs infection, but only wild-type BUN was able to suppress signaling downstream of IRF-3. Studies with a BUN minireplicon system showed that active replication induced an IRF-3-dependent promoter, which was suppressed by the NSs protein. In a cell line (P2.1) defective in double-stranded RNA signaling due to low levels of IRF-3, induction of apoptosis was similar for wild-type BUN and BUNdelNSs. These data suggest that the BUN NSs protein can delay cell death in the early stages of BUN infection by inhibiting IRF-3-mediated apoptosis.

scholarly journals Interferon regulatory factor 1 inactivation in human cancer

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Khaldoon Alsamman ◽  
Omar S. El-Masry
Keyword(s):  
Inflammatory Responses ◽  
Current Knowledge ◽  
Human Cancer ◽  
Tumor Biology ◽  
Interferon Regulatory Factor ◽  
Potential Importance ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Related Proteins ◽  
The Impact

Interferon regulatory factors (IRFs) are a group of closely related proteins collectively referred to as the IRF family. Members of this family were originally recognized for their roles in inflammatory responses; however, recent research has suggested that they are also involved in tumor biology. This review focusses on current knowledge of the roles of IRF-1 and IRF-2 in human cancer, with particular attention paid to the impact of IRF-1 inactivation. The different mechanisms underlying IRF-1 inactivation and their implications for human cancers and the potential importance of IRF-1 in immunotherapy are also summarized.

scholarly journals Attaching and Effacing Bacterial Effector NleC Suppresses Epithelial Inflammatory Responses by Inhibiting NF-κB and p38 Mitogen-Activated Protein Kinase Activation

2011 ◽  
Vol 79 (9) ◽  
pp. 3552-3562 ◽  
Author(s):  
Ho Pan Sham ◽  
Stephanie R. Shames ◽  
Matthew A. Croxen ◽  
Caixia Ma ◽  
Justin M. Chan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Loop Model ◽  
Wild Type ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
The Impact

ABSTRACTEnteropathogenicEscherichia coli(EPEC) and enterohemorrhagicE. coliare noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-κB nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by ΔnleCEPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-κB and p38 mitogen-activated protein kinase (MAPK) activation. UsingCitrobacter rodentium, a mouse-adapted A/E bacterium, we found that ΔnleCand wild-typeC. rodentium-infected mice carried similar pathogen burdens, yet ΔnleCstrain infection led to worsened colitis. Similarly, infection with ΔnleCC. rodentiumin a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.

scholarly journals Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells

2004 ◽  
Vol 200 (2) ◽  
pp. 247-253 ◽  
Author(s):  
Michael Lohoff ◽  
Hans-Willi Mittrücker ◽  
Anne Brüstle ◽  
Frank Sommer ◽  
Bärbel Casper ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Leishmania Major ◽  
Protozoan Parasite ◽  
Interferon Regulatory Factor ◽  
Wild Type ◽  
Regulatory Factor ◽  
Cd4 Cells ◽  
Th Cells ◽  
Th Cell

Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4+ T helper (Th) cells lacking IRF4 (IRF4−/−) are highly sensitive to apoptosis. After infection of IRF4−/− mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4−/− CD4+ Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4−/− and IRF4+/+ CD4+ cells did not increase survival of IRF4−/− CD4+ cells, indicating that the enhanced rate of IRF4−/− Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4+ cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4−/− and IRF4+/+ cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4−/− CD4+ cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4+ cells against proapoptotic stimuli.

Altered Immune Response of Interferon Regulatory Factor 1-Deficient Mice against Plasmodium berghei Blood-Stage Malaria Infection

1999 ◽  
Vol 67 (5) ◽  
pp. 2277-2283 ◽  
Author(s):  
Rosemary Sok-Pin Tan ◽  
Chiguang Feng ◽  
Yoshihiro Asano ◽  
Anna Ursula Kara
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Plasmodium Berghei ◽  
Interferon Regulatory Factor ◽  
Blood Stage ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
In The Wild ◽  
Ifn Γ

ABSTRACT Nitric oxide (NO) is a short-lived biological mediator which can be induced in various cell types and is able to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of NO production by transcriptional upregulation of inducible nitric oxide synthase. In the present study, we used mice devoid of functional interferon regulatory factor 1 by targeted gene disruption (IRF-1−/−) to investigate the role of NO in the host immune response against blood-stage Plasmodium berghei ANKA infection. IRF-1−/− mice survived longer with a later onset of and a lower peak parasitemia despite the inability to produce appreciable levels of NO. The administration of exogenous interleukin-12 (IL-12) was able to prolong survival in the wild-type mice with an upregulation in the expression of both gamma interferon (IFN-γ) and NO. However, the administration of IL-12 did not improve the survival of IRF-1−/− mice. These studies indicate that while IL-12 is able to mediate protection via an IFN-γ- and NO-dependent pathway in the wild-type mice, such a protective mechanism may not be functional in the IRF-1−/− mice. Our results suggest that NO may not be essential for host immunity to the parasite and that IRF-1−/− mice are able to induce an IFN-γ- and NO-independent mechanism against P. berghei infection.

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