Anti-high mobility group box 1 antibody suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury

Abstract

BackgroundRefractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. Anti-inflammatory treatment using steroids is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that steroids can induce side effects. The present study examines if the inhibition of proinflammatory cytokine, high mobility group box 1 (HMGB1), can facilitate olfactory functional recovery following injury.MethodsOlfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. We measured HMGB1 gene expression in the olfactory bulb using semi-quantitative polymerase chain reaction (PCR) assays and examined HMGB1 protein localization in the olfactory bulb using immunohistochemical staining. Anti-HMGB1 antibody was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using both an olfactory avoidance behavioral test and evoked potential recording.ResultsHMGB1 gene and protein were significantly expressed in the olfactory bulb 12 h after NTx. Anti-HMGB1 antibody-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia and an increase in regenerating nerve fibers. Both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in the anti-HMGB1 antibody-injected mice.ConclusionsThese findings suggest that inhibition of HMGB1 could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.

Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching

“…We believe that this therapeutic effect is caused by a lower level of HMGB1; previous studies have shown that elevated levels of HMGB1 are highly correlated with glial cell activation [41]. Previous literature also reports that the neutralization of HMGB1 in the diabetic spinal cord and transcended olfactory nerve with a neutralizing antibody reduces the production of GFAP [42,43]. TM can sequester HMGB1 through its lectin-like domain; therefore, we consider that this mechanism might be responsible for the lower levels of GFAP in TM-treated nerves.…”

NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression

“…Many studies have reported that HMGB1, as an important latestage inflammatory mediator, is an important therapeutic target for infectious diseases such as sepsis-associated encephalopathy and autoimmune encephalomyelitis (Uzawa et al, 2013) at an early stage. It has been reported that the expression of HMGB1 increases approximately 12 h following TBI, spinal cord injury, and cerebral hemorrhage, and that anti-HMGB1 therapy can reduce brain edema, inhibit neuroinflammation, and restore neurological dysfunction (Okuma et al, 2012;Haruma et al, 2016;Wang et al, 2017;Kobayashi et al, 2018). However, HMGB1 almost returned to the baseline level 2-4 weeks after injury according to published data (Kigerl et al, 2018).…”

High-Dose Immunoglobulin G Suppresses Local Inflammatory Reaction and Facilitates Functional Recovery Following Olfactory System Injury

“…The advantage of using these mice is that a histological assessment of degenerating and regenerating olfactory nerve bers can be performed using a standard method for staining and light microscopy. Although the functional signi cance of OMP is not fully understood, previous studies have shown that OMP-tau-lacZ mice are capable of recovering olfactory function after olfactory nerve injury [13][14][15].…”

“…To determine if olfactory function recovered after the NTx, a smell detection test using avoidance conditioning behavior to cycloheximide was administered to mice before and after the NTx as reported previously [13][14][15]. Cycloheximide has a peculiar odor and unpleasant taste for mice.…”

“…We previously reported using an olfactory nerve injury model in mice that anti-in ammatory treatment with steroids, cytokine antagonists as anti-interleukin-6 (IL-6) receptor antibody and tumor necrosis factor (TNF)-α blocker, and anti-high mobility group box 1 (HMGB1) antibody during acute phase of injury is effective in suppressing the in ammatory reaction and local glial scar formation and improves recovery outcomes after olfactory nerve transection (NTx) [12][13][14][15]. In clinical practice, however, these drugs are not typically used for the treatment of head injury patients.…”