Blockade of interleukin-6 receptor suppresses inflammatory reaction and facilitates functional recovery following olfactory system injury

Kobayashi, Masayoshi; Tamari, Kengo; Miyamura, Tomotaka; Takeuchi, Kazuhiko

doi:10.1016/j.neures.2013.03.015

Cited by 22 publications

(30 citation statements)

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“…We have previously demonstrated that the line 19 stain of RSV used in the current study induces expression of IL-6 [18], an inflammatory cytokine that suppress OE regeneration following injury [24]. Since the loss of SOX2 + ORN progenitors by RSV infection occurs as early as day 2, and virus specific immune responses require several days before effector T cells are seen at the site of infection, it is unlikely that cytokines produced by effector T cells are responsible for the damage to SOX2 + ORN progenitors.…”

Section: Discussionmentioning

confidence: 99%

Viral disruption of olfactory progenitors is exacerbated in allergic mice

Ueha

Mukherjee

Ueha

et al. 2014

International Immunopharmacology

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Upper airway viral infection in patients with airway allergy often exacerbates olfactory dysfunction, but the mechanism for this exacerbation remains unclear. Here, we examined the effects of respiratory syncytial virus (RSV) infection, in the presence or absence of airway allergy, on olfactory receptor neurons (ORNs) and their progenitors in mice. Immunohistological analyses revealed that cockroach allergen (CRA)-induced airway allergy alone did not affect the number of OMP+ mature ORNs and SOX2+ ORN progenitors. Intranasal RSV line 19 infection in allergy-free mice resulted in a transient decrease in SOX2+ ORN progenitors without affecting OMP+ ORNs. In contrast, the RSV-induced decrease in SOX2+ ORN progenitors was exacerbated and prolonged in allergic mice, which resulted in eventual loss of OMP+ ORNs. In the allergic mice, reduction of RSV in the olfactory epithelium was delayed as compared with allergy-free mice. These results suggest that ORN progenitors were impaired by RSV infection and that airway allergy exacerbated damage to ORN progenitors by reducing viral clearance.

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Section: Discussionmentioning

confidence: 99%

Viral disruption of olfactory progenitors is exacerbated in allergic mice

Ueha

Mukherjee

Ueha

et al. 2014

International Immunopharmacology

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“…The advantage of using these mice is that a histological assessment of degenerating and regenerating olfactory nerve fibers can be performed using a standard method for staining and light microscopy. Although the exact function of OMP and effects of lack of OMP has not been revealed yet, many previous studies have shown that OMP-tau-lacZ mice are capable of recovering olfactory function after olfactory nerve injury [ 13 , 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…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 ]. Cycloheximide has a peculiar odor and unpleasant taste for mice.…”

Section: Methodsmentioning

confidence: 99%

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

Kobayashi

Tamari

Salihi

et al. 2018

J Neuroinflammation

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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.

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“…In addition, blockage of specific pathways mediating the inflammatory response could also provide a new strategy for the treatment of posttraumatic olfactory dysfunction. Interleukin-6 reduces astrocytes and macrophages in the areas of olfactory injury and contributes to improved olfactory nerve regeneration and recovery [82].…”

Section: Prognosismentioning

confidence: 99%