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

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.