Fr‑HMGB1 and ds‑HMGB1 activate the kynurenine pathway via different mechanisms in association with depressive‑like behavior

Abstract

Our previous study reported that fully reduced high mobility group box 1 (fr-HMGB1) and disulfide HMGB1 (ds-HMGB1) induce depressive-like behavior; however, the underlying mechanisms remain unclear. In the present study, the induction of depression via the kynurenine pathway by different redox states of HMGB1 was investigated in vivo and in vitro . To evaluate the expression of enzymes of the kynurenine pathway, reverse transcription-quantitative PCR and western blot analyses were conducted. Additionally, cytokine levels were measured by ELISAs. Following intracerebroventricular injection of ds- and fr-HMGB1, behavioral tests were performed, revealing the presentation of depressive-like behavior, and essential proteins in the kynurenine pathway were demonstrated to be upregulated at the mRNA level, suggesting that ds- and fr-HMGB1 contributed to the development of this behavior via the kynurenine pathway. ds-HMGB1 directly activated the kynurenine pathway and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampal tissue. Conversely, fr-HMGB1 upregulated the aforementioned factors only following treatment with H 2 O 2 . These findings indicated that ds-HMGB1 induced depression in a manner associated with the kynurenine pathway, whereas oxidation of fr-HMGB1 evoked activation of the kynurenine pathway, resulting in depressive behavior.

Curcumin Ameliorates Chronic Mild Stress-Induced Depressive-Like Behavior via HMGB1/TLR4/NF-κB Signaling Pathway

“…HMBG1 has become a hotspot of in ammation research because of its pro-in ammatory effect, acting as a strong mediator of in ammation linking infection and tissue damage [33]. In CUMS mice, the hippocampus [48] cerebral cortex [32] expressed high levels of HMGB1. Depression-like behavior can be induced by stress via NFκB/TLR4/HMGB1 signaling in the hippocampus [48].…”

“…Excess HMGB1 in the extracellular space binds with many receptors on the cell surface, such as Toll-like receptor 4 (TLR4) [30], and plays a crucial part in chronic and acute in ammation pathogenesis (e.g., in autoimmune diseases, atherosclerosis, cancer, and sepsis) [26]. Increased HMGB1 levels in the central and peripheral nervous systems were observed in mice displaying symptoms of depression, leading to the proposal that that HMGB1 drives depression resulting from chronic stress [31,32]. Moreover, in ammation mediated by HMGB1 in depressive-like behaviors might involve an imbalance between neurotoxic and neuroprotective factors, dysregulated kynurenine signaling, proin ammatory cytokines, and the Nod-like receptor family pyrin domain containing three (NLRP3) in ammasome [33].…”

Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression

“…The two forms of the alarmin protein, high mobility group box-1 (HMGB1)—the fully reduced (fr-HMGB1) and the disulfide (ds-HMGB1) form—are known to induce depressive-like behavior [ 150 ]. Recently, it has been shown in mouse hippocampal tissues ds-HMGB1 directly activated IDO, KMO, and KYNU in parallel with IL-1β upregulation [ 151 ]. With fr-HMGB1, the same observations were made following H 2 O 2 treatment.…”

“…The two forms of the high mobility group box-1 (HMGB1) protein (fr-HMGB1 and ds-HMGB1) mentioned regarding IL-1β cytokine, are also known to upregulate TNFα besides inducing depressive-like behavior [ 150 ]. Additionally, alongside IL-β, TNFα was also upregulated in mice hippocampal tissues in parallel with IDO, KMO, and KYNU, which were activated by both forms of HMGB1 [ 151 ].…”

LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein

“…Interestingly, subsequent studies have shown that exogenous icv HMGB1-pretreatment or endogenously produced HMGB1 after induction of sterile inflammation (turpentine) exacerbated LPS-induced reduced social exploration [6] or fever [33], respectively. Similarly, even severe psychological stress or aging can induce the release of HMGB1 from microglia and neurons in the brain leading to a brain inflammatory response accompanied by depressive-like symptoms [34][35][36] and to a primed, enhanced immune and sickness response in aged rats to subsequent Escherichia coli infection [37].…”