VLCAD deficiency related chronic inflammation pattern is suggestive of systemic mediators

Authors:

Megan Beck, PhD, University of Tennessee Health Science Center, Memphis, TN, USA

Angel Lin, BS, University of Tennessee Health Science Center, Memphis, TN, USA

Josh Michel, MS, University of Pittsburgh, School Med, Pittsburgh, PA, USA

Abbe Vallejo, PhD, University of Pittsburgh, School Med, Pittsburgh, PA, USA

Jerry Vockley, MD, University of Pittsburgh, School Med, Pittsburgh, PA, USA

Henry Mroczkowski, MD, PhD, University of Tennessee Health Science Center, Memphis, TN, USA

Corresponding Author Contact Information:

Megan Beck, MBeck10@UTHSC.edu  , +01-901-287-4475

  1. Joel Mroczkowski, Mroczkowski@UTHSC.edu , +01-901-287-6465

Abstract:

 

Background and Objectives: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a life-threatening disorder of mitochondrial fatty acid oxidation. Newborn screening with early intervention provides the best opportunity to prevent morbidity and mortality. Anaplerotic energy supplementation therapy has been shown to be effective in treating hypoglycemia; however, rhabdomyolysis episodes and atypical chronic inflammation often persist. We hypothesize that rhabdomyolysis susceptibility is associated with maladaptive systemic inflammation that is independent of energy deficiency.

Materials and Methods: We analyzed pathways with Ingenuity and Pathway Commons programs to correlate previously observed cytokines and proteins that link inflammation and VLCAD deficiency phenotype. Bone marrow was collected from C57BL/6 and VLCAD-/- mice at 10 weeks of life to create in vitro monocytes/macrophages (Mf) and dendritic cells (DCs). We then stimulated inflammatory pathways in half of the cells with lipopolysaccharide (LPS). Spent media was collected, and cytokine profiles were analyzed by a custom 17-Plex (CRP, IFN-g, IL-1a, IL-1β, IL-4, IL-12p70, IL-13, IL-17A,

IL-23p19, IL-33, MCP-1, M-CSF, MIP-1a, MIP-1β, S100A8, S100A9, and TNFa) Luminex Assay (R&D Systems, LXSAMSM17).

Results: In LPS treated VLCAD-/- Mf, IL-12p70 and IL-23p19 were significantly elevated compared to wild type (WT). Otherwise VLCAD-/- cytokine levels were lower or not significantly different from WT.

Discussion/Conclusion: Our results show that in vitro inflammatory changes occur in Mf and DCs from VLCAD-/- mice that distinguish them from WT controls. Increased production of IL-12p70 and IL- 23p19 by LPS-stimulated VLCAD-/- Mf cells as compared to WT further supports proposed monocyte-activation related mechanism. Additional differences may be explained by cell-specific production and age-dependent increase of cytokines. Current results were found in primary cell culture from 10-week-old mice in comparison to prior data on 6-month-old mouse plasma. We will explore these postulates through time-course measurements of cytokines in mouse plasma. Considering the hypothesis that inflammation contributes to episodes of rhabdomyolysis; clearly chronic inflammation does play a role in VLCAD deficiency and offers a therapeutic target with optimized immune modulators (e.g. infliximab) that could significantly improve patient quality of life.

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