# Quantitative Proteomic Analysis Indicates That Pggt1b Deficiency Promotes Cytokine Secretion in Resiquimod‐Stimulated Bone Marrow‐Derived Macrophages via the NF‐κB Pathway

## TL;DR

This study shows that reduced PGGT1B in macrophages increases inflammation via the NF-κB pathway, which may contribute to psoriasis.

## Contribution

The study reveals a novel role of Pggt1b in regulating cytokine secretion through the NF-κB pathway in psoriasis-related macrophages.

## Key findings

- Pggt1b deficiency increases cytokine production in R848-stimulated macrophages.
- Six hub proteins were identified as key in Pggt1b-mediated inflammation.
- Pggt1b regulates inflammation via the NF-κB pathway in macrophages.

## Abstract

Psoriasis is a systemic inflammatory skin disease mediated by the innate and adaptive immune systems. Recent studies have indicated that macrophages may contribute to the pathogenesis of psoriasis. However, the role of macrophage protein geranylgeranyl transferase type‐1β subunit (PGGT1B) in psoriasis is unclear. In this study, we aimed to establish how a reduction in Pggt1b expression in monocytes influences the onset and progression of psoriasis.

Myeloid cell‐specific Pggt1b knockout mice were generated, and their bone marrow‐derived macrophages (BMDMs) were stimulated with resiquimod (R848) to mimic the psoriatic immune microenvironment. The proteomic analysis enabled us to identify 17 differentially expressed proteins associated with Pggt1b deficiency in the psoriasis macrophage model (folded change ≥ 1.3 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment was performed. Quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and western blot assays were used to verify the differentially expressed proteins and signaling pathways. Finally, an enzyme‐linked immunosorbent assay was used to verify the expression of the key inflammatory cytokine interleukin (IL)‐1β.

In total, six proteins (Dlgap5, Fas, Fnta, Nlrp3, Cd14, and Ticam2) were identified as hub proteins. Furthermore, we found that Pggt1b might mediate R848‐induced inflammation via the small G‐proteins Rac1 or Cdc42. We found that Pggt1b positively regulates pro‐inflammatory responses in R848‐stimulated BMDMs via the NF‐κB signaling pathway.

This study clarified that PGGT1B affected the synthesis of inflammatory cytokines via NF‐κB pathway and provided insights into the mechanisms underlying immune responses and inflammation.

In Pggt1b‐deficient macrophages, TLR4 may be in a highly activated state and can be activated by R848 or DAMPS, which strongly correlated with increased cytokine production, interferon‐γ production, augmented amide binding and transferase activity, and the activation of NF‐κB and/or Nlrp3 inflammasome pathways.