Limits...
IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis.

Li B, Gurung P, Malireddi RK, Vogel P, Kanneganti TD, Geiger TL - Nat Commun (2015)

Bottom Line: However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity.IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1β to IL-1β.Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennesse 38105, USA.

ABSTRACT
Polymorphisms attenuating IL-10 signalling confer genetic risk for inflammatory bowel disease. Yet, how IL-10 prevents mucosal autoinflammation is incompletely understood. We demonstrate using lineage-specific deletions of IL-10Rα that IL-10 acts primarily through macrophages to limit colitis. Colitis depends on IL-6 to support pathologic Th17 cell generation in wild-type mice. However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1β to IL-1β. Therefore, lineage-specific effects of IL-10 skew the cytokine dependency of Th17 cell development required for colitis pathogenesis. Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.

No MeSH data available.


Related in: MedlinePlus

Cytokine production by colonic macrophages(A) Colons from Rag1−/− andIL-10RαMdelRag1−/− mice, 8 wkafter colitis induction, were homogenized and cytokines (IL-1β, IL-6,TNF-α, MCP-1, IL-10, IL-17 and IFN-γ) measured by ELISA ormultiplex assay. Results from individual mice (circles) and cohort means (lines)are plotted. (B and C) Percent and absolute number of IL-17+and IFN-γ+ cells among CD4+ Tcells from colons of diseased mice (8 wk). (D) Relative expression of theindicated mRNAs (IL-1β, IL-6, IL-23p19 and iNOS) from LPMϕs,DCs, neutrophils and epithelial cells sorted from colon tissue and measured byqRT-PCR. (E) Relative expression of the indicated mRNAs (TNF-α, IL-17,IL-12p40, IL-10, and arginase) from LPMϕs sorted from colon tissue andmeasured by qRT-PCR. Data are representative of three independent experiments,n=10 per cohort. *, p<0.05; **, p<0.01,***, p<0.001 (by t-test).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4302761&req=5

Figure 4: Cytokine production by colonic macrophages(A) Colons from Rag1−/− andIL-10RαMdelRag1−/− mice, 8 wkafter colitis induction, were homogenized and cytokines (IL-1β, IL-6,TNF-α, MCP-1, IL-10, IL-17 and IFN-γ) measured by ELISA ormultiplex assay. Results from individual mice (circles) and cohort means (lines)are plotted. (B and C) Percent and absolute number of IL-17+and IFN-γ+ cells among CD4+ Tcells from colons of diseased mice (8 wk). (D) Relative expression of theindicated mRNAs (IL-1β, IL-6, IL-23p19 and iNOS) from LPMϕs,DCs, neutrophils and epithelial cells sorted from colon tissue and measured byqRT-PCR. (E) Relative expression of the indicated mRNAs (TNF-α, IL-17,IL-12p40, IL-10, and arginase) from LPMϕs sorted from colon tissue andmeasured by qRT-PCR. Data are representative of three independent experiments,n=10 per cohort. *, p<0.05; **, p<0.01,***, p<0.001 (by t-test).

Mentions: To further evaluate the heightened disease severity inIL-10RαMdelRag1−/− mice, wemeasured in whole colons the levels of cytokines implicated in its pathogenesis,including IL-1β, IL-6, TNF-α, MCP-1, IL-10, IL-17, andIFN-γ31. Withearly disease (wk 4), IL-1β, IL-6, and MCP-1 were increased inIL-10RαMdelRag1−/− coloncompared with Rag1−/− controls (Fig. 4a). As disease progressed (wk 8), the quantityof cytokine produced was altered. Additional elevations in IL-17 andTNF-α were identified at this time. Differences in IL-10 andIFN-γ were not seen.


IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis.

Li B, Gurung P, Malireddi RK, Vogel P, Kanneganti TD, Geiger TL - Nat Commun (2015)

Cytokine production by colonic macrophages(A) Colons from Rag1−/− andIL-10RαMdelRag1−/− mice, 8 wkafter colitis induction, were homogenized and cytokines (IL-1β, IL-6,TNF-α, MCP-1, IL-10, IL-17 and IFN-γ) measured by ELISA ormultiplex assay. Results from individual mice (circles) and cohort means (lines)are plotted. (B and C) Percent and absolute number of IL-17+and IFN-γ+ cells among CD4+ Tcells from colons of diseased mice (8 wk). (D) Relative expression of theindicated mRNAs (IL-1β, IL-6, IL-23p19 and iNOS) from LPMϕs,DCs, neutrophils and epithelial cells sorted from colon tissue and measured byqRT-PCR. (E) Relative expression of the indicated mRNAs (TNF-α, IL-17,IL-12p40, IL-10, and arginase) from LPMϕs sorted from colon tissue andmeasured by qRT-PCR. Data are representative of three independent experiments,n=10 per cohort. *, p<0.05; **, p<0.01,***, p<0.001 (by t-test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4302761&req=5

Figure 4: Cytokine production by colonic macrophages(A) Colons from Rag1−/− andIL-10RαMdelRag1−/− mice, 8 wkafter colitis induction, were homogenized and cytokines (IL-1β, IL-6,TNF-α, MCP-1, IL-10, IL-17 and IFN-γ) measured by ELISA ormultiplex assay. Results from individual mice (circles) and cohort means (lines)are plotted. (B and C) Percent and absolute number of IL-17+and IFN-γ+ cells among CD4+ Tcells from colons of diseased mice (8 wk). (D) Relative expression of theindicated mRNAs (IL-1β, IL-6, IL-23p19 and iNOS) from LPMϕs,DCs, neutrophils and epithelial cells sorted from colon tissue and measured byqRT-PCR. (E) Relative expression of the indicated mRNAs (TNF-α, IL-17,IL-12p40, IL-10, and arginase) from LPMϕs sorted from colon tissue andmeasured by qRT-PCR. Data are representative of three independent experiments,n=10 per cohort. *, p<0.05; **, p<0.01,***, p<0.001 (by t-test).
Mentions: To further evaluate the heightened disease severity inIL-10RαMdelRag1−/− mice, wemeasured in whole colons the levels of cytokines implicated in its pathogenesis,including IL-1β, IL-6, TNF-α, MCP-1, IL-10, IL-17, andIFN-γ31. Withearly disease (wk 4), IL-1β, IL-6, and MCP-1 were increased inIL-10RαMdelRag1−/− coloncompared with Rag1−/− controls (Fig. 4a). As disease progressed (wk 8), the quantityof cytokine produced was altered. Additional elevations in IL-17 andTNF-α were identified at this time. Differences in IL-10 andIFN-γ were not seen.

Bottom Line: However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity.IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1β to IL-1β.Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennesse 38105, USA.

ABSTRACT
Polymorphisms attenuating IL-10 signalling confer genetic risk for inflammatory bowel disease. Yet, how IL-10 prevents mucosal autoinflammation is incompletely understood. We demonstrate using lineage-specific deletions of IL-10Rα that IL-10 acts primarily through macrophages to limit colitis. Colitis depends on IL-6 to support pathologic Th17 cell generation in wild-type mice. However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1β to IL-1β. Therefore, lineage-specific effects of IL-10 skew the cytokine dependency of Th17 cell development required for colitis pathogenesis. Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.

No MeSH data available.


Related in: MedlinePlus