Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Immunometabolism

• Inborn errors of immunity

Main Findings

The primary question addressed in this study was whether patients with inborn fatty acid oxidation disorders exhibit alterations in their ability to respond to LPS stimulation. The study was performed on primary dermal fibroblasts from patients with ETFDH or ACADVL enzyme deficiencies, crucial enzymes in the fatty acid oxidation pathway. The authors observed that these fibroblasts from patients show impairment in the TLR4 signalling pathway, resulting in a reduced release of IL-6 and other pro-inflammatory cytokines in response to LPS stimulation.

Limitations

• The study would benefit from including more biological replicates in their experiments, for instance for the experiments with ETFDH enzyme deficient patients the sample size was only n = 2. However, we acknowledge that it is quite difficult to find patients with these rare inborn disorders.

• Some of the results appear inconsistent, even within a single figure. For instance, in Figure 1 secreted cytokines measurement does not correspond to what is shown with qPCR, this could happen for various reasons. It would help drawing conclusions if this was explained in more detail, why the authors find these differences.

• The study would benefit for understanding better the variability of data that all patient data are shown. For instance, in Figure 3 panel B the measurement of secreted IL-6 is shown for patients P5-P8, but for IL-1β it was only patients P7 and P8. Thus, it would be helpful for consistency reasons that all patients are shown or the same ones ideally.

• Clear labelling of axes could be improved

• Currently the manuscript would benefit from further proof-reading to avoid spelling errors

• The current version of the manuscript lacks some clear innovation or more orthogonal approaches to their findings, while it is noted that using primary patient samples is an important aspect to clinical research.

• The study could benefit from alternative in vitro models or even an in vivo model to strengthen the authors conclusions and to allow for mechanistic investigations. It would be very interesting to see if the same impairment of response to LPS is observed in macrophages/dendritic cells.

Significance/Novelty

This study enhances our understanding of key proteins involved in fatty acid beta-oxidation, specifically ETFDH and ACADAVL, and their role in regulating innate immune responses. One notable aspect of the study is that it utilized primary dermal fibroblasts from patients with these enzyme deficiencies. We believe that the discovery of these proteins' involvement in LPS response regulation is an exciting development that could serve as inspiration for future research.

While the study provides valuable evidence, there are still unanswered questions about how these enzymes influence the LPS response. For example, it remains to be explored at which point in the signaling cascade the response is interrupted, preventing the elicitation of the LPS response. The evidence provided suggests potential mechanisms for these processes, but the exact involvement of ETFDH and ACADAVL has not been conclusively demonstrated. Additionally, it would be interesting to investigate potential interacting partners of ETFDH and ACADAVL and determine whether their influence on TLR4 signaling is indirect.

Lastly, the study highlights an intriguing finding: the TLR3 response differs between two patient groups. Understanding the mechanisms behind these distinct outcomes would be a valuable area for further investigation.

Credit

Reviewed by Deborah Gil and Alisa Iakupova as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Charité Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.