LPS-induced systemic inflammation is suppressed by the PDZ motif peptide of ZO-1 via regulation of macrophage M1/M2 polarization

Reviewer #1 (Public Review):

Summary:

In this study, the authors investigate the potential therapeutic effects of the PEGylated PDZ peptide, derived from the ZO-1 protein, in suppressing LPS-induced systemic inflammation. The authors found that the pretreatment of PEGylated PDZ peptide led to a restoration of tissue injuries in the kidney, liver, and lung, and diminished alterations in biochemical plasma markers induced by LPS. This was accompanied by decreased production of pro-inflammatory cytokines in the plasma and lung BALF of the PDZ-administered mice.

Strengths:

- The data presented here is solid and the results provide the groundwork for developing novel anti-inflammatory therapeutic strategies.
- The authors employ various cells and in vivo models to test the efficacy of the peptide.

Weaknesses:
The mechanism of action remains largely unknown.

Reviewer #2 (Public Review):

Summary:

The authors investigated systemic inflammation induced by LPS in various tissues and also examined immune cells of the mice using tight junction protein-based PDZ peptide. They explored the mechanism of anti-systemic inflammatory action of PDZ peptides, which enhanced M1/M2 polarization and induced the proliferation of M2 macrophages. Additionally, they insisted on the physiological mechanism that inhibited the production of ROS in mitochondria, thereby preventing systemic inflammation.

Strengths:
In the absence of specific treatments for septic shock or sepsis, the study demonstrating that tight junction-based PDZ peptides inhibit systemic inflammation caused by LPS is highly commendable. Whereas previous research focused on antibiotics, this study proves that modifying parts of intracellular proteins can significantly suppress symptoms caused by septic shock. The authors expanded the study of localized inflammation caused by LPS or PM2.5 in the respiratory tract, to systemic inflammation, presenting promising results. They not only elucidated the physiological mechanism by identifying the transcriptome through RNA sequencing but also demonstrated that PDZ peptides inhibit the production of ROS in mitochondria and prevent mitochondrial fission. This research is highly regarded as an excellent study with potential as a treatment for septic shock or sepsis.

Weaknesses
(1) The authors focused intensively on acute inflammation for a short duration instead of chronic inflammation.
(2) LPS was used to induce septic shock, but administrating actual microbes such as E.coli would yield more accurate results.
(3) The authors used pegylated peptides, but future research should utilize the optimized peptides to derive the optimal peptide, and further, PK/PD studies are also necessary.