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Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation.

Ip WK, Medzhitov R - Nat Commun (2015)

Bottom Line: Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various adaptation responses.Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice.Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

ABSTRACT
Interstitial osmolality is a key homeostatic variable that varies depending on the tissue microenvironment. Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various adaptation responses. Hyperosmolality due to high dietary salt intake has been linked to pathological inflammatory conditions. Little is known about the mechanisms of sensing the hyperosmotic stress by the innate immune system. Here we report that caspase-1 is activated in macrophages under hypertonic conditions. Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice. Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.

No MeSH data available.


Related in: MedlinePlus

Inflammasome activation promotes Th17 response in mice on high-salt diet. (a–c) Wild-type mice (C57BL/6) or caspase-1-deficient mice (Caspase-1 KO) fed high-salt or control diet (each group, n = 9) were immunized with OVA/LPS for 7 days. Single-cell suspension prepared from draining lymph nodes was analyzed for Il17a and Ifng mRNA expression by qRT-PCR (a) or intracellular IL-17A production in CD4+ T cells by FACS (b), or re-stimulated in vitro with the indicated concentrations of OVA for 2 days and supernatants were analyzed for IL-17A by ELISA (c). Data are mean ± s.d. for pooled group of mice. Contour plots of FACS analysis show the percentages of IL-17-producing CD4+ T cells. Student’s t test: *, P ≤ 0.05, **, P ≤ 0.01, ***, P ≤ 0.001.
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Figure 7: Inflammasome activation promotes Th17 response in mice on high-salt diet. (a–c) Wild-type mice (C57BL/6) or caspase-1-deficient mice (Caspase-1 KO) fed high-salt or control diet (each group, n = 9) were immunized with OVA/LPS for 7 days. Single-cell suspension prepared from draining lymph nodes was analyzed for Il17a and Ifng mRNA expression by qRT-PCR (a) or intracellular IL-17A production in CD4+ T cells by FACS (b), or re-stimulated in vitro with the indicated concentrations of OVA for 2 days and supernatants were analyzed for IL-17A by ELISA (c). Data are mean ± s.d. for pooled group of mice. Contour plots of FACS analysis show the percentages of IL-17-producing CD4+ T cells. Student’s t test: *, P ≤ 0.05, **, P ≤ 0.01, ***, P ≤ 0.001.

Mentions: High dietary salt (NaCl) intake has been associated with pathological conditions including enhanced inflammation in humans and mice. Recent studies in animals have shown that high-salt diets can lead to interstitial hypertonic salt accumulation in skin 37, and promote tissue inflammation by enhancing Th17 cell differentiation in lymphoid tissues in mice with experimental autoimmune encephalomyelitis (EAE)38, 39. The Th17 differentiation was dependent on T cell expression of the salt induced serum glucocorticoid kinase 1 (SGK1)38, 39. Given our findings that hypertonic stress promotes IL-1β production and the established role of IL-1β in Th17 differentiation 40, we asked whether inflammasome-mediated salt-sensing mechanism in tissue compartments is involved in the induction of Th17 response in vivo. To address this, we examined whether caspase-1 is required for the Th17 polarization in mice maintained on high-salt diet. Consistent with the previous studies 38, 39, we observed enhanced Th17 response in high-salt diet mice immunized with OVA/LPS. Specifically, we detected increased Il17a but not Ifng mRNA expression and higher numbers of IL-17A-expressing CD4+ T cells in draining lymph nodes from wild-type mice fed high-salt diet as compared to controls (Fig. 7a,b). Furthermore, draining lymph node cells from wild-type mice on high-salt diet showed significantly enhanced IL-17A but not IFN-γ cytokine secretion upon OVA re-stimulation in vitro (Fig. 7c and Supplementary Fig. 18), indicating enhanced in vivo induction of antigen-specific Th17 cells. Most importantly, these enhancements of Th17 response by high-salt diet were abolished in caspase-1-deficient mice (Fig. 7a–c), indicating that caspase-1 activation is required for the enhanced Th17 response. These data support the idea that inflammasome activation plays an important physiological role in sensing hypertonic salt accumulation in tissue compartments and promoting Th17 responses.


Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation.

Ip WK, Medzhitov R - Nat Commun (2015)

Inflammasome activation promotes Th17 response in mice on high-salt diet. (a–c) Wild-type mice (C57BL/6) or caspase-1-deficient mice (Caspase-1 KO) fed high-salt or control diet (each group, n = 9) were immunized with OVA/LPS for 7 days. Single-cell suspension prepared from draining lymph nodes was analyzed for Il17a and Ifng mRNA expression by qRT-PCR (a) or intracellular IL-17A production in CD4+ T cells by FACS (b), or re-stimulated in vitro with the indicated concentrations of OVA for 2 days and supernatants were analyzed for IL-17A by ELISA (c). Data are mean ± s.d. for pooled group of mice. Contour plots of FACS analysis show the percentages of IL-17-producing CD4+ T cells. Student’s t test: *, P ≤ 0.05, **, P ≤ 0.01, ***, P ≤ 0.001.
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Figure 7: Inflammasome activation promotes Th17 response in mice on high-salt diet. (a–c) Wild-type mice (C57BL/6) or caspase-1-deficient mice (Caspase-1 KO) fed high-salt or control diet (each group, n = 9) were immunized with OVA/LPS for 7 days. Single-cell suspension prepared from draining lymph nodes was analyzed for Il17a and Ifng mRNA expression by qRT-PCR (a) or intracellular IL-17A production in CD4+ T cells by FACS (b), or re-stimulated in vitro with the indicated concentrations of OVA for 2 days and supernatants were analyzed for IL-17A by ELISA (c). Data are mean ± s.d. for pooled group of mice. Contour plots of FACS analysis show the percentages of IL-17-producing CD4+ T cells. Student’s t test: *, P ≤ 0.05, **, P ≤ 0.01, ***, P ≤ 0.001.
Mentions: High dietary salt (NaCl) intake has been associated with pathological conditions including enhanced inflammation in humans and mice. Recent studies in animals have shown that high-salt diets can lead to interstitial hypertonic salt accumulation in skin 37, and promote tissue inflammation by enhancing Th17 cell differentiation in lymphoid tissues in mice with experimental autoimmune encephalomyelitis (EAE)38, 39. The Th17 differentiation was dependent on T cell expression of the salt induced serum glucocorticoid kinase 1 (SGK1)38, 39. Given our findings that hypertonic stress promotes IL-1β production and the established role of IL-1β in Th17 differentiation 40, we asked whether inflammasome-mediated salt-sensing mechanism in tissue compartments is involved in the induction of Th17 response in vivo. To address this, we examined whether caspase-1 is required for the Th17 polarization in mice maintained on high-salt diet. Consistent with the previous studies 38, 39, we observed enhanced Th17 response in high-salt diet mice immunized with OVA/LPS. Specifically, we detected increased Il17a but not Ifng mRNA expression and higher numbers of IL-17A-expressing CD4+ T cells in draining lymph nodes from wild-type mice fed high-salt diet as compared to controls (Fig. 7a,b). Furthermore, draining lymph node cells from wild-type mice on high-salt diet showed significantly enhanced IL-17A but not IFN-γ cytokine secretion upon OVA re-stimulation in vitro (Fig. 7c and Supplementary Fig. 18), indicating enhanced in vivo induction of antigen-specific Th17 cells. Most importantly, these enhancements of Th17 response by high-salt diet were abolished in caspase-1-deficient mice (Fig. 7a–c), indicating that caspase-1 activation is required for the enhanced Th17 response. These data support the idea that inflammasome activation plays an important physiological role in sensing hypertonic salt accumulation in tissue compartments and promoting Th17 responses.

Bottom Line: Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various adaptation responses.Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice.Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

ABSTRACT
Interstitial osmolality is a key homeostatic variable that varies depending on the tissue microenvironment. Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various adaptation responses. Hyperosmolality due to high dietary salt intake has been linked to pathological inflammatory conditions. Little is known about the mechanisms of sensing the hyperosmotic stress by the innate immune system. Here we report that caspase-1 is activated in macrophages under hypertonic conditions. Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice. Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.

No MeSH data available.


Related in: MedlinePlus