DcR3 Suppresses Lipopolysaccharide-Induced Aggresome-like Structures in Macrophages via Inhibition of Reactive Oxygen Species and p38 MAPK

Decoy receptor 3 (DcR3) is a pleiotropic soluble factor that modulates cellular functions through both decoy and non-decoy mechanisms. DcR3 has been reported to exert anti-apoptotic and anti-inflammatory effects in humans, particularly in cancers and inflammatory diseases. In the present study, we investigated the role of DcR3 in TLR4-mediated innate immune responses in macrophages. Because the DcR3 gene is absent in the mouse genome, we generated myeloid-specific DcR3 knock-in mice and isolated bone marrow-derived macrophages (BMDMs) for functional analyses. Our results showed that DcR3 did not significantly affect LPS-induced expression of COX-2, iNOS, NLRP3, or pro-IL-1β. Aggresome-like induced structures (ALIS), which consist of aggregates of ubiquitinated proteins, are stress-induced cytoplasmic compartments implicated in MHC class I antigen presentation. We found that DcR3 suppressed LPS-induced ALIS formation by attenuating cellular reactive oxygen species production and p38 MAPK activation. In addition to LPS stimulation, DcR3 also reduced the accumulation of ubiquitinated proteins induced by HO-1 inhibitor ZnPP, lysosomal inhibitor bafilomycin A1, and proteasomal inhibitor MG132. Consistent with a role for autophagy in ALIS regulation, rapamycin reduced LPS-induced ALIS formation, whereas bafilomycin A1 induced comparable LC3-II accumulation in both wild-type and DcR3-expressing macrophages. Furthermore, DcR3 expression did not significantly alter LPS-induced p62 or HO-1 expression. Collectively, although DcR3 does not markedly influence LPS-induced inflammatory responses in BMDMs, our findings reveal a previously unrecognized role for DcR3 in suppressing ALIS formation and the accumulation of ubiquitinated proteins in macrophages, thereby suggesting a novel function for DcR3 in maintaining intracellular protein homeostasis under stress conditions.