Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

Jung, Camille; Meinzer, Ulrich; Montcuquet, Nicolas; Thachil, Élodie; Château, Danielle; Thiébaut, Raphaële; Roy, Maryline; Alnabhani, Ziad; Berrebi, Dominique; Dussaillant, Monique; Pédruzzi, Eric; Thenet, Sophie; Cerf‐Bensussan, Nadine; Hugot, Jean‐Pierre; Barreau, Frédérick

doi:10.1172/jci58147

Cited by 46 publications

(32 citation statements)

References 58 publications

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“…Based on our results, and contrary to the conclusions of some previous studies (32), NF-κB inhibition may be deleterious in patients with mucositis. We show that pro-IL-1β can be produced independently of NF-κB, and its processing and secretion will be augmented by the inflammasome activation via NF-κB inhibition (24).…”

Section: Discussioncontrasting

confidence: 97%

Critical role for IL-1β in DNA damage-induced mucositis

Kanarek¹,

Grivennikov

Leshets³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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β-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-κB inhibitor IκB. To appreciate tissue-specific roles of β-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1β as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1β is induced by DNA damage via an NF-κB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-κB, with failure to express the endogenous IL-1β receptor antagonist IL-1Ra upon fourallele loss. Antibody neutralization of IL-1β prevents epithelial tight junction dysfunction and alleviates mucositis in β-TrCP-deficient mice. IL-1β antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.

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Section: Discussioncontrasting

confidence: 97%

Critical role for IL-1β in DNA damage-induced mucositis

Kanarek¹,

Grivennikov

Leshets³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in contraction of the actin-myosin ring, subsequently increasing permeability at the cell-cell junction (35). MLCK activation is commonly seen with bacterial infection, leading to alterations in tight junctions (36,37). MLCK activation is also associated with increases in IL-6, TNF and IL-1β that further activate MLCK.…”

Section: Introductionmentioning

confidence: 99%

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Lorentz

Liang

Meng

et al. 2017

Mol Med

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Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK -/-and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK -/-mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK -/-mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK -/-mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK -/-mice; however, survival was similar between septic MLCK -/-mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

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“…Although all TLRs share many common functions, further research has shown that individual TLR signaling pathways diverge and have unique functions. For instance, during intestinal bacterial infection, TLR2 activation may increase the severity of intestinal barrier disruption through a specific effect on the permeability of epithelial tight junctions in the intestine (4). In sharp contrast, TLR9 expressed on antigen-presenting cells (APCs) is essential for APC expansion in the mesenteric lymph nodes of mice during infection (5).…”

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confidence: 99%

Toll-Like Receptor 2 (TLR2) and TLR9 Play Opposing Roles in Host Innate Immunity against Salmonella enterica Serovar Typhimurium Infection

et al. 2015

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bToll-like receptors (TLRs) are evolutionarily conserved host proteins that are essential for effective host defense against pathogens. However, recent studies suggest that some TLRs can negatively regulate immune responses. We observed here that TLR2 and TLR9 played opposite roles in regulating innate immunity against oral infection of Salmonella enterica serovar Typhimurium in mice. While TLR9 ؊/؊ mice exhibited shortened survival, an increased cytokine storm, and more severe Salmonella hepatitis than wild-type (WT) mice, TLR2 ؊/؊ mice exhibited the opposite phenomenon. Further studies demonstrated that TLR2 deficiency and TLR9 deficiency in macrophages both disrupted NK cell cytotoxicity against S. Typhimurium-infected macrophages by downregulating NK cell degranulation and gamma interferon (IFN-␥) production through decreased macrophage expression of the RAE-1 NKG2D ligand. But more importantly, we found that S. Typhimurium-infected TLR2 ؊/؊ macrophages upregulated inducible nitric oxide synthase (iNOS) expression, resulting in a lower bacterial load than that in WT macrophages in vitro and livers in vivo as well as low proinflammatory cytokine levels. In contrast, TLR9 ؊/؊ macrophages showed decreased reactive oxygen species (ROS) expression concomitant with a high bacterial load in the macrophages and in livers of TLR9؊/؊ macrophages were also more susceptible than WT macrophages to S. Typhimurium-induced necroptosis in vitro, likely contributing to bacterial spread and transmission in vivo. Collectively, these findings indicate that TLR2 negatively regulates anti-S. Typhimurium immunity, whereas TLR9 is vital to host defense and survival against S. Typhimurium invasion. TLR2 antagonists or TLR9 agonists may thus serve as potential anti-S. Typhimurium therapeutic agents. During the early stages of infection, the innate immune system serves as the first line of defense against microbial replication and spread before an adaptive response is mounted (1). As one mechanism to elicit a rapid and appropriate innate immune response against pathogen infection, pattern recognition receptors (PRRs) evolved in the host to recognize various microbial molecular patterns. In response, pathogens evolved to use many different tactics, including subversion of some of these host antimicrobial immune mechanisms, in order to ensure their multiplication, survival, and persistence in the host (2). This ongoing interplay between host innate immune responses and pathogen virulence factors largely determines the outcome of most infections.As the most widely studied PRRs, Toll-like receptors (TLRs) play a crucial role in pathogen recognition and the induction of immune responses. Currently, 11 and 13 TLRs have been identified in humans and mice, respectively. They are widely expressed on many cell types, such as macrophages, neutrophils, dendritic cells (DCs), and mucosal epithelial cells. TLR signaling results in the induction of reactive oxygen species (ROS) and the activation of the transcription factor NF-B, which in turn induce...

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Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

Cited by 46 publications

References 58 publications

Critical role for IL-1β in DNA damage-induced mucositis

Critical role for IL-1β in DNA damage-induced mucositis

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Toll-Like Receptor 2 (TLR2) and TLR9 Play Opposing Roles in Host Innate Immunity against Salmonella enterica Serovar Typhimurium Infection

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