LPS-induced systemic inflammation is suppressed by the PDZ motif peptide
of ZO-1 via regulation of macrophage M1/M2 polarization
Abstract
Background and Purpose: The Gram-negative bacterium lipopolysaccharide
(LPS) is frequently administered to generate models of systemic
inflammation. In particular, both kidney and lung are more sensitive to
acute injury caused by LPS-induced systemic inflammation. However, there
are several side effects and no effective treatment for LPS-induced
systemic inflammation. Experimental approach: The PEGylated PDZ peptide
was synthesized based on the PDZ motif of ZO-1 protein. We investigated
the anti-inflammatory effect of PEGylated PDZ peptide on LPS-induced
systemic inflammation in mice. We also performed the RNA-Sequencing
analysis to know the expression pattern of 24,424 genes according to
each comparison combination. Key Results: PDZ peptide administration led
to restoration of tissue injuries (kidney, liver, and lung) and
prevented alterations in biochemical plasma markers. The production of
pro-inflammatory cytokines was significantly decreased in the plasma and
lung BALF in the PDZ-administered mice. Flow cytometry analysis revealed
the PDZ peptide significantly inhibited inflammation, mainly by
decreasing the population of M1 macrophages, neutrophils, and increasing
M2 macrophages. Using RNA sequencing analysis, the expression levels of
the NF-κB-related proteins were lower in PDZ-treated cells than in
LPS-treated cells. Wild-type PDZ peptide significantly increased
mitochondrial membrane integrity and decreased LPS-induced mitochondria
fission. PDZ peptide dramatically could reduce LPS-induced NF-κB
signaling, ROS production, and the expression of M1 macrophage marker
proteins, but increased the expression of M2 macrophage marker proteins.
Conclusion and Implication: These results indicated PEGylated PDZ
peptide inhibits LPS-induced systemic inflammation, reducing tissue
injuries and reestablishing homeostasis and may be a therapeutic
candidate against systemic inflammation.