Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits

Defective autophagy has been associated with proinflammatory diseases, yet the mechanisms through which autophagy mitigates inflammation remain unclear. In this study, we discovered that the pan-FGFR inhibitor LY2874455 effectively activates autophagy and reduces the expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Through multiplex proteomic profiling, we identified the immunoproteasome—a specific isoform of the 20S constitutive proteasome—as a substrate degraded by selective autophagy. We found that SQSTM1/p62 serves as a selective autophagy-related receptor mediating this degradation.

When autophagy was deficient or p62 was knocked down, the effects of LY2874455 were blocked, resulting in the accumulation of immunoproteasomes and heightened inflammatory responses. The expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, underscoring the critical role of immunoproteasome turnover in autophagy-mediated suppression of proinflammatory factor expression.

In vivo, LY2874455 demonstrated protective effects against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis, leading to low levels of proinflammatory cytokines and immunoproteasomes. These findings suggest that the selective autophagy of the immunoproteasome is a key regulator of signaling in the innate immune system.