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Sterol biosynthesis regulates TLR signaling and the innate immune response in a Smith-Lemli-Opitz syndrome model
Kristin Gabor, … , Forbes D. Porter, Michael B. Fessler
Kristin Gabor, … , Forbes D. Porter, Michael B. Fessler
Published January 18, 2024
Citation Information: J Clin Invest. 2024;134(6):e167633. https://doi.org/10.1172/JCI167633.
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Research Letter Immunology Inflammation Article has an altmetric score of 2

Sterol biosynthesis regulates TLR signaling and the innate immune response in a Smith-Lemli-Opitz syndrome model

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Abstract

Authors

Kristin Gabor, Emily V. Mesev, Jennifer Madenspacher, Julie Meacham, Prashant Rai, Sookjin Moon, Christopher A. Wassif, Saame Raza Shaikh, C.J. Tucker, Peer Karmaus, Simona Bianconi, Forbes D. Porter, Michael B. Fessler

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Figure 1

Attenuated TLR signaling in SLOS.

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Attenuated TLR signaling in SLOS.
(A) Fibroblasts from individuals actin...
(A) Fibroblasts from individuals acting as controls (n = 2) and patients with SLOS (n = 4) were stimulated, and media were assayed for cytokines. (B) Fibroblast IL-6 production rank ordered by clinical severity score. (C) Whole blood was LPS stimulated and assayed for cytokines (n = 7–11). (D) Peritoneal macrophages from mice of indicated genotypes were stimulated (HKLM, heat-killed L. monocytogenes) and TNF-α in media was quantified. (E–I) RAW 264.7 macrophages were treated with vehicle or BM15.766 (BM), stained with Alexa Fluor 488–cholera toxin subunit B (CtB), and imaged for (E) total intensity, (F) CtB+ foci/cell, and (G) clustering of foci. (H and I) Signal for (H) fPEG-cholesterol and (I) anti-TLR4 antibody was quantified. (J) Macrophages pretreated with vehicle/BM were LPS stimulated. MyD88 immunoprecipitates (IP) and whole cell lysates (WCL) were immunoblotted for indicated targets. (K) Bronchoalveolar lavage neutrophils (PMN) quantified 24 hours after K. pneumoniae lung infection in mice of indicated genotypes (n = 7–12). (L) qPCR for indicated targets in mouse lungs 3 days after infection with influenza A virus (n = 3–5). Data represent mean ± SEM and are representative of 2–3 independent experiments. In C and L, boxes depict the 25th–75th percentile around median; whiskers represent the minimum and maximum. #P = 0.05; *P < 0.05; **P < 0.01; ***P < 0.001 (unpaired 2-tailed t test for all except 1-way ANOVA with Dunnett’s post test for K).

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