# Sequestosome-1/p62 Mediates TLR4-Induced Inflammatory Program in Dendritic Cells Under Normoxic and Hypoxic Conditions

## TL;DR

This study shows that p62 helps control inflammation in immune cells through TLR4 signaling, both in normal and low-oxygen conditions.

## Contribution

The study reveals p62's role in TLR4-induced inflammation in dendritic cells under normoxic and hypoxic conditions.

## Key findings

- LPS induces p62 overexpression and enhances its interaction with RIP1 regardless of oxygen levels.
- Inhibiting p62's ZZ-domain reduces NFκB activation and IL-1β production in dendritic cells.
- p62 is critical for TLR4-mediated inflammation in both physiological and pathological environments.

## Abstract

Sequestosome-1/p62, a multifunctional adaptor protein, plays a critical role in NFκB signaling. In response to Toll-like receptor 4 (TLR4) activation, p62 facilitates NFκB activation via its interaction with RIP1, a process dependent on the p62 ZZ-domain. Dendritic cells (DCs), key mediators of immune responses, express a diverse array of TLRs, and their activation triggers DC maturation and pro-inflammatory cytokine secretion, including IL-1β, through NFκB signaling. Given that DCs encounter varying oxygen tensions during their lifespan, their adaptability to hypoxia is crucial. We previously demonstrated that p62 contributes to DC survival under hypoxic stress, through its crosstalk with ERK1/2. Here, we investigated the role of p62 in lipopolysaccharide (LPS)-induced inflammatory responses in DCs exposed to both normoxic and hypoxic environments. Our findings revealed that LPS induces p62 overexpression and enhanced its interaction with RIP1, regardless of oxygen levels. Furthermore, pharmacological inhibition of p62 ZZ-domain, using XRK3F2, significantly attenuated p62/RIP1 interaction, resulting in diminished NFκB activation and IL-1β production. These results highlight p62 as a critical regulator of TLR4-mediated inflammatory program in DCs in either physiological or pathological microenvironments and thus suggesting novel therapeutic targets in inflammation.

The online version contains supplementary material available at 10.1007/s00018-025-05989-y.