Toll-like receptor-4 dependent intestinal gene expression during Arcobacter butzleri infection of gnotobiotic IL-10 deficient mice

Gölz, Greta; Alter, Thomas; Bereswill, Stefan; Heimesaat, Markus M.

doi:10.1556/1886.2016.00006

Cited by 5 publications

(5 citation statements)

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“…Moreover, following peroral infection of conventional adult mice with Arcobacter butzleri sharing taxonomic relationships to Campylobacterales, cytokines of the IL-23/IL-22/IL-18 axis were regulated not only in a strain and time course of infection, but also tissue dependent fashion. Whereas in the colon IL-22 and IL-18 were up-regulated upon A. butzleri infection, IL-23p19 and IL-22 mRNA levels increased in the small intestines of infected conventional adult WT mice [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Following infection of differentiated THP-1 macrophages with an adherent and invasive C. concisus strain, genes encoding IL-23 and IL-18, but not IL-22, were regulated as assessed by transcriptomic and proteomic analyses [ 40 ]. Our previous A. butzleri infection studies in gnotobiotic IL-10 −/− mice further revealed that in the colon IL-18 mRNA levels were elevated during both the early and late phase of infection, whereas colonic IL-22 mRNA was upregulated during the former only [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

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The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection

et al. 2016

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BackgroundHuman Campylobacter jejuni infections are worldwide on the rise. Information about the distinct molecular mechanisms underlying campylobacteriosis, however, are scarce. In the present study we investigated whether cytokines including IL-23, IL-22 and IL-18 sharing pivotal functions in host immunity were involved in mediating immunopathological responses upon C. jejuni infection.ResultsTo address this, conventionally colonized IL-23p19−/−, IL-22−/− and IL-18−/− mice were perorally infected with C. jejuni strain ATCC 43431. Respective gene-deficient, but not wildtype mice were susceptible to C. jejuni infection and could be readily colonized with highest pathogenic loads in the terminal ileum and colon at day 14 postinfection (p.i.). In IL-23p19−/−, IL-22−/− and IL-18−/− mice viable C. jejuni were detected in MLNs, but did not translocate to spleen, liver, kidney and blood in the majority of cases. Susceptible IL-22−/−, but neither IL-23p19−/−, nor IL-18−/− mice harbored higher intestinal commensal E. coli loads when compared to resistant wildtype mice. Alike C. jejuni, commensal E. coli did not translocate from the intestinal to extra-intestinal tissue sites. Despite C. jejuni infection, mice lacking IL-23p19, IL-22 or IL-18 exhibited less apoptotic cells, but higher numbers of proliferating cells in their colonic epithelium as compared to wildtype mice at day 14 p.i. Less pronounced apoptosis was parallelled by lower abundance of neutrophils within the colonic mucosa and lamina propria of infected IL-23p19−/− and IL-22−/− as compared to wildtype control mice, whereas less distinct colonic TNF secretion could be measured in IL-22−/− and IL-18−/− than in wildtype mice at day 14 p.i. Notably, in infected IL-22−/− mice, colonic IL-23p19 mRNA levels were lower, whereas the other way round, colonic IL-22 expression rates were lower in IL-23p19−/− mice as compared to wildtype controls. Moreover, IL-18 mRNA was less distinctly expressed in large intestines of naive and infected IL-22−/− mice, but not vice versa, given that IL-22 mRNA levels did not differ between in IL-18−/− and wildtype mice.ConclusionCytokines belonging to the IL-23/IL-22/IL-18 axis mediate immunopathological responses upon murine C. jejuni infection in a differentially orchestrated manner. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogenic-host interaction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-016-0106-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection

et al. 2016

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“…jejuni [ 17 ], IL-18, but also IL-22 were up-regulated in the large intestines of A . butzleri infected mice [ 36 , 37 ]. As shown by us [ 16 , 17 ] and others [ 38 ], the Th-17 cytokines IL-17A, IL-22 and IFN-γ increased in the intestines of C .…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice

et al. 2016

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BackgroundHuman Campylobacter jejuni infections are progressively rising worldwide. Information about the molecular mechanisms underlying campylobacteriosis, however, are limited. In the present study we investigated whether cytokines such as IL-23, IL-22 and IL-18, which share pivotal functions in host immunity, were involved in mediating intestinal and systemic immunopathological responses upon C. jejuni infection.Methodology/Principal FindingsTo assure stable infection, gnotobiotic (i.e. secondary abiotic) IL-23p19-/-, IL-22-/- and IL-18-/- mice were generated by broad-spectrum antibiotic treatment. Following peroral C. jejuni strain 81–176 infection, mice of all genotypes harbored comparably high pathogenic loads in their intestines. As compared to wildtype controls, however, IL-18-/- mice displayed less distinct C. jejuni induced sequelae as indicated by less pronounced large intestinal shrinkage and lower numbers of apoptotic cells in the colonic epithelial layer at day 8 postinfection (p.i.). Furthermore, lower colonic numbers of adaptive immune cells including regulatory T cells and B lymphocytes were accompanied by less distinct secretion of pro-inflammatory cytokines such as TNF and IFN-γ and lower IL-17A mRNA expression levels in colonic ex vivo biopsies of infected IL-18-/- as compared to wildtype mice. Upon C. jejuni infection, colonic IL-23p19 expression was up-regulated in IL-18-/- mice only, whereas IL-22 mRNA levels were lower in uninfected and infected IL-23p19-/- as well as infected IL-18-/- as compared to respective wildtype control mice. Remarkably, not only intestinal, but also systemic infection-induced immune responses were less pronounced in IL-18-/- mice as indicated by lower TNF, IFN-γ and IL-6 serum levels as compared to wildtype mice.Conclusion/SignificanceWe here show for the first time that IL-18 is essentially involved in mediating C. jejuni infection in the gnotobiotic mouse model. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogen-host interaction.

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“…In our study, colonic mucin-2 mRNA expression was in fact downregulated, but in IL-22 –/– infant mice only. We could recently show that C. jejuni infection of conventionally colonized adult IL-10 –/– mice was accompanied by a decrease in intestinal mucin-2 mRNA expression [ 22 ], which was also true for Arcobacter butzleri- infected gnotobiotic (i.e., secondary abiotic) IL-10 –/– animals [ 23 , 24 ]. Downregulated mucin-2 expression in the large intestines of IL-22 –/– mice at day 6 p.i.…”

Section: Discussionmentioning

confidence: 99%

“…IL-23 has been highlighted as a master regulator of mucosal immune responses upon intestinal infection and inflammation [ 29 ]. We have recently shown that, following Arcobacter butzleri infection, IL-23 was upregulated depending on the respective strain, the intestinal compartment, and the time course of infection [ 24 ]. Furthermore, in acute Toxoplasma gondii- induced ileitis, immunopathology was characterized by an IL-23-dependent upregulation of both IL-22 and MMP-2, leading to small intestinal necrosis [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Colonic Expression of Genes Encoding Inflammatory Mediators and Gelatinases During Campylobacter Jejuni Infection of Conventional Infant Mice

Heimesaat

Grundmann

Alutis

et al. 2016

EuJMI

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Within 1 week following peroral Campylobacter jejuni infection, infant mice develop acute enteritis resolving thereafter. We here assessed colonic expression profiles of mediators belonging to the IL-23/IL-22/IL-18 axis and of matrix-degrading gelatinases MMP-2 and MMP-9 at day 6 post C. jejuni strain 81-176 infection. Whereas the pathogen readily colonized the intestines of infant IL-18–/– mice only, colonic mucin-2 mRNA, a pivotal mucus constituent, was downregulated in IL-22–/– mice and accompanied by increased expression of pro-inflammatory cytokines including IFN-γ, TNF, IL-17A, and IL-1β. Furthermore, in both naive and infected IL-22–/– mice, colonic expression of IL-23p19 and IL-18 was lower as compared to wildtype mice, whereas, conversely, colonic IL-22 mRNA levels were lower in IL-18–/– and colonic IL-18 expression lower in IL-23p19–/– as compared to wildtype mice. Moreover, colonic expression of MMP-2 and MMP-9 and their endogenous inhibitor TIMP-1 were lower in IL-22–/– as compared to wildtype mice at day 6 postinfection. In conclusion, mediators belonging of the IL-23/IL-22/IL-18 axis as well as the gelatinases MMP-2 and MMP-9 are involved in mediating campylobacteriosis of infant mice in a differentially regulated fashion.

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Toll-like receptor-4 dependent intestinal gene expression during Arcobacter butzleri infection of gnotobiotic IL-10 deficient mice

Cited by 5 publications

References 50 publications

The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection

The IL-23/IL-22/IL-18 axis in murine Campylobacter jejuni infection

Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice

Colonic Expression of Genes Encoding Inflammatory Mediators and Gelatinases During Campylobacter Jejuni Infection of Conventional Infant Mice

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