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The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity.

Heinz LX, Baumann CL, Köberlin MS, Snijder B, Gawish R, Shui G, Sharif O, Aspalter IM, Müller AC, Kandasamy RK, Breitwieser FP, Pichlmair A, Bruckner M, Rebsamen M, Blüml S, Karonitsch T, Fauster A, Colinge J, Bennett KL, Knapp S, Wenk MR, Superti-Furga G - Cell Rep (2015)

Bottom Line: Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis.Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling.Taken together, our results identify the membrane-modulating enzyme SMPDL3B as a negative regulator of TLR signaling that functions at the interface of membrane biology and innate immunity.

View Article: PubMed Central - PubMed

Affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus

SMPDL3B Is a Negative Regulator of Inflammation In Vivo(A and B) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected with 50 μg LPS i.p. After 6 hr, mice were sacrificed, and (A) peritoneal lavage was taken and total cells and neutrophils were counted, and (B) serum IL-6 and TNF were measured by ELISA.(C) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected i.p. with 1 × 104 cfu of E. coli. After 6 hr, mice were sacrificed, and the serum cytokine levels of IL-6, TNF, IL-12p40, KC, IL-10, and IL-1β were analyzed by ELISA. Bars are means of each group ± SEM (∗p ≤ 0.05) and are representative of two independent experiments, each performed with eight mice/group.
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fig5: SMPDL3B Is a Negative Regulator of Inflammation In Vivo(A and B) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected with 50 μg LPS i.p. After 6 hr, mice were sacrificed, and (A) peritoneal lavage was taken and total cells and neutrophils were counted, and (B) serum IL-6 and TNF were measured by ELISA.(C) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected i.p. with 1 × 104 cfu of E. coli. After 6 hr, mice were sacrificed, and the serum cytokine levels of IL-6, TNF, IL-12p40, KC, IL-10, and IL-1β were analyzed by ELISA. Bars are means of each group ± SEM (∗p ≤ 0.05) and are representative of two independent experiments, each performed with eight mice/group.

Mentions: If, as all evidence so far would show, SMPDL3B is involved in homeostasis of membrane lipid composition and TLR signaling, then it should have a role in TLR-mediated inflammatory processes in vivo. To assess this, we used an LPS-dependent mouse inflammation model. Wild-type or Smpdl3b-deficient mice were injected intraperitoneally with LPS and peritoneal cell influx as well as serum cytokine levels were determined 6 hr later (Figures 5A and 5B). Smpdl3b-deficient mice contained higher numbers of immune cells in the peritoneal lavage fluid (PLF), due to a significantly enhanced influx of neutrophils, in line with an aberrantly strong inflammatory response (Figure 5A). Concomitantly, Smpdl3b-deficient mice showed increased IL-6 levels in the serum as compared to control mice (Figure 5B). Serum levels of TNF were not significantly affected under these conditions (Figure 5B). To test whether SMPDL3B also affects the host-response against viable pathogens, we used an E. coli-induced peritonitis model. Hence, wild-type and Smpdl3b-deficient mice were injected with bacteria in the peritoneum and serum cytokine levels were quantified 6 hr later. Serum levels of IL-6, TNF, IL-12p40, and KC were significantly elevated in Smpdl3b-deficient mice as compared to wild-type (Figure 5C). Interestingly, we did not detect significant alterations in the serum levels of the cytokines IL-10 and IL-1β, indicating that not all inflammatory mediators were equally affected by Smpdl3b deficiency (Figure 5C). Taken together, our experiments indeed establish SMPDL3B as negative regulator of TLR-dependent inflammatory responses in vivo.


The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity.

Heinz LX, Baumann CL, Köberlin MS, Snijder B, Gawish R, Shui G, Sharif O, Aspalter IM, Müller AC, Kandasamy RK, Breitwieser FP, Pichlmair A, Bruckner M, Rebsamen M, Blüml S, Karonitsch T, Fauster A, Colinge J, Bennett KL, Knapp S, Wenk MR, Superti-Furga G - Cell Rep (2015)

SMPDL3B Is a Negative Regulator of Inflammation In Vivo(A and B) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected with 50 μg LPS i.p. After 6 hr, mice were sacrificed, and (A) peritoneal lavage was taken and total cells and neutrophils were counted, and (B) serum IL-6 and TNF were measured by ELISA.(C) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected i.p. with 1 × 104 cfu of E. coli. After 6 hr, mice were sacrificed, and the serum cytokine levels of IL-6, TNF, IL-12p40, KC, IL-10, and IL-1β were analyzed by ELISA. Bars are means of each group ± SEM (∗p ≤ 0.05) and are representative of two independent experiments, each performed with eight mice/group.
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fig5: SMPDL3B Is a Negative Regulator of Inflammation In Vivo(A and B) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected with 50 μg LPS i.p. After 6 hr, mice were sacrificed, and (A) peritoneal lavage was taken and total cells and neutrophils were counted, and (B) serum IL-6 and TNF were measured by ELISA.(C) Wild-type (WT) and Smpdl3b-deficient (KO) mice were injected i.p. with 1 × 104 cfu of E. coli. After 6 hr, mice were sacrificed, and the serum cytokine levels of IL-6, TNF, IL-12p40, KC, IL-10, and IL-1β were analyzed by ELISA. Bars are means of each group ± SEM (∗p ≤ 0.05) and are representative of two independent experiments, each performed with eight mice/group.
Mentions: If, as all evidence so far would show, SMPDL3B is involved in homeostasis of membrane lipid composition and TLR signaling, then it should have a role in TLR-mediated inflammatory processes in vivo. To assess this, we used an LPS-dependent mouse inflammation model. Wild-type or Smpdl3b-deficient mice were injected intraperitoneally with LPS and peritoneal cell influx as well as serum cytokine levels were determined 6 hr later (Figures 5A and 5B). Smpdl3b-deficient mice contained higher numbers of immune cells in the peritoneal lavage fluid (PLF), due to a significantly enhanced influx of neutrophils, in line with an aberrantly strong inflammatory response (Figure 5A). Concomitantly, Smpdl3b-deficient mice showed increased IL-6 levels in the serum as compared to control mice (Figure 5B). Serum levels of TNF were not significantly affected under these conditions (Figure 5B). To test whether SMPDL3B also affects the host-response against viable pathogens, we used an E. coli-induced peritonitis model. Hence, wild-type and Smpdl3b-deficient mice were injected with bacteria in the peritoneum and serum cytokine levels were quantified 6 hr later. Serum levels of IL-6, TNF, IL-12p40, and KC were significantly elevated in Smpdl3b-deficient mice as compared to wild-type (Figure 5C). Interestingly, we did not detect significant alterations in the serum levels of the cytokines IL-10 and IL-1β, indicating that not all inflammatory mediators were equally affected by Smpdl3b deficiency (Figure 5C). Taken together, our experiments indeed establish SMPDL3B as negative regulator of TLR-dependent inflammatory responses in vivo.

Bottom Line: Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis.Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling.Taken together, our results identify the membrane-modulating enzyme SMPDL3B as a negative regulator of TLR signaling that functions at the interface of membrane biology and innate immunity.

View Article: PubMed Central - PubMed

Affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus