Work

Exosomes from joints mediate depressive-like behaviors in MIA arthritis mice

Year: 2026

Type: article

Abstract: Arthritis-related mood disturbances suggest pathogenic communication between inflamed joints and the brain, yet the causal mediators remain unclear. Here we show that exosomes released from mono-iodoacetate (MIA)–injured knees transmit surface-displayed high mobility group box 1 (HMGB1) to the brain, where they activate neuronal NF-κB and senescence programs that culminate in depressive-like behavior. In mice with MIA arthritis, depressive-like behaviours (reduced sucrose/saccharin preference) coincided with increased neuronal pp65 and senescence markers. Pharmacologic exosomes inhibition (GW4869) prevented both molecular and behavioral phenotypes, while intravenous transfer of purified joint-derived exosomes from MIA donors recapitulated them in naïve recipients. A proteinase-K protection assay localized HMGB1 to the exosomes exterior, and neutralizing HMGB1 with 2G7 abrogated exosome-induced neuronal pp65/senescence and restored behavioral performance without altering joint histopathology. In vitro, joint-derived exosomes triggered HMGB1-dependent NF-κB activation and senescence signatures in primary neurons, supporting neuron-intrinsic responsiveness to vesicular DAMP signaling. These data identify a joint-to-brain exosome/HMGB1 axis as both necessary and sufficient to drive affective dysfunction after MIA. Our findings propose a tractable therapeutic framework—intercepting exosomes biogenesis/trafficking or neutralizing circulating HMGB1—to mitigate mood symptoms associated with arthritis. More broadly, the work illustrates how tissue-restricted inflammation can remodel distant neural circuits via vesicle-borne danger signals, offering biomarker and intervention opportunities for inflammatory disorders complicated by affective disturbances. • Joint-derived exosomes from MIA knees induce depressive-like behavior in mice • Exosomes carry surface HMGB1 that crosses the BBB and triggers brain senescence • Blocking exosome release with GW4869 prevents depressive-like and aging phenotypes • Neutralizing exosomal HMGB1 with 2G7 reverses brain senescence and anhedonia • HMGB1 exosomes activate neuronal NF-κB and promote microglial pro-inflammation state polarization

Source: Brain Research Bulletin

DOI: 10.1016/j.brainresbull.2026.111929

Authors: Zonghao Li, Yiming Gao, Hongpeng Ma, Yang Xiong, Jian Wang, Guangzhi Ning