The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity

• Published in: Cell reports (Cambridge) Vol. 11; no. 12; pp. 1919 - 1928
• Main Authors: Heinz, Leonhard X., Baumann, Christoph L., Köberlin, Marielle S., Snijder, Berend, Gawish, Riem, Shui, Guanghou, Sharif, Omar, Aspalter, Irene M., Müller, André C., Kandasamy, Richard K., Breitwieser, Florian P., Pichlmair, Andreas, Bruckner, Manuela, Rebsamen, Manuele, Blüml, Stephan, Karonitsch, Thomas, Fauster, Astrid, Colinge, Jacques, Bennett, Keiryn L., Knapp, Sylvia, Wenk, Markus R., Superti-Furga, Giulio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2015; Cell Press; Elsevier
• Subjects: Animals; Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 3 - immunology; Disease Models, Animal; Humans; Immunity, Innate - genetics; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Life Sciences; Lipids - immunology; Macrophages - immunology; Mice; Peritonitis - genetics; Peritonitis - immunology; Peritonitis - pathology; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.05.006

Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis. Activation of Toll-like receptors (TLRs) leads to a complex cellular response, orchestrating a diverse range of inflammatory events that need to be tightly controlled. Here, we identified the GPI-anchored Sphingomyelin Phosphodiesterase, Acid-Like 3B (SMPDL3B) in a mass spectrometry screening campaign for membrane proteins co-purifying with TLRs. Deficiency of Smpdl3b in macrophages enhanced responsiveness to TLR stimulation and profoundly changed the cellular lipid composition and membrane fluidity. Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling. Finally, Smpdl3b-deficient mice displayed an intensified inflammatory response in TLR-dependent peritonitis models, establishing its negative regulatory role in vivo. 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. [Display omitted] •Identification of SMPDL3B as lipid-modulating phosphodiesterase on macrophages•Negative regulatory role for SMPDL3B in Toll-like receptor function•Strong influence of SMPDL3B on membrane lipid composition and fluidity•Smpdl3b-deficient mice show enhanced responsiveness in TLR-dependent peritonitis Heinz et al. identify the lipid-modulating phosphodiesterase SMPDL3B as negative regulator of Toll-like receptor function. Smpdl3b-deficiency strongly affected macrophage lipid composition and fluidity and led to higher responsiveness to TLR stimulation. Peritonitis models in Smpdl3b-deficient mice confirmed the negative regulatory role in vivo.