CD38 coordinates with NF-κB to promote cochlear inflammation in noise-induced hearing loss：the protective effect of Apigenin

doi:10.21203/rs.3.rs-2730360/v1

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CD38 coordinates with NF-κB to promote cochlear inflammation in noise-induced hearing loss：the protective effect of Apigenin

https://doi.org/10.21203/rs.3.rs-2730360/v1

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Noise exposure is one of the most common scause of sensorineural hearing loss. Although a large number of studies considered inflammation as a major contributor to noise-induced hearing loss, the process of cochlear inflammation is still unclear. Studies have found that activation of the NF-κB signal caused the accumulation of macrophages in the inner ear plays an important role in hair cell damage. In this study, Tandem Mass Tag (TMT) technique was used to analyze the changes of basilar membrane proteome expression before and after acoustic injury. After noise exposure, Nicotinamide Adenine Dinucleotide (NAD) metabolism level was down-regulated and NF-κB signal pathway was activated. It seemed that the expression of CD38, the main NAD hydrolase in mammals, could straightly lead to the inflammation onset. Then Anakinra, an IL-1 receptor blocker, and Apigenin, a CD38 inhibitor, were given to animals to protect noise induced hearing loss. Our results showed that Anakinra had a littlt influence on the hearing threshold shift, while Apigenin could significantly reduce the threshold shift of hearing by inhibiting the activation of NF-κB and CD38. These results suggest that inhibition of the expression of NF-κB and CD38 can be a promising target for protecting noise-induced hearing loss.

Noise-induced hearing loss is caused by multiple components, including direct mechanical damage of hair cells, and dysfunction of cochlear microvascular circulation metabolic homeostasis ^{[1, 2]}. An increasing number of researchers have considered cochlear inflammation to be one of the crucial causes of hair cell damage ^[3]. NF-κB signaling pathway, which is related to immune cell activation and inflammatory factor release, is one of the inflammatory pathways involved in cochlear inflammation. Previously, it is reported that NLRP3 inflammasome and related inflammatory factors are involved in noise-induced hearing loss^[4]. Some of studies have suggested that the activation of macrophages is a vital part of cochlear inflammation.

It is still unclear what’s the function of cochlear immune cells. and how the macrophages work in cochlea. Lang et al. found that the resident immune cells of the cochlear are rooted in hematopoietic stem cells^[5] and the innate immune system of the cochlea plays an important role in maintaining the normal structure and function of the cochlear^[6]. CD38 which is expressed on the surface of lymphocytes, monocytes, macrophages, dendritic cells and natural killer cells is considered as the signal of immune cell activation^[7]. It has a chemotactic effect on leukocyte aggregation^[8]. Recent studies found that CD38 is the main nicotinamide adenine dinucleotide (NAD) hydrolase in mammals, which can transform NAD into adenosine diphosphate ribose (ADPR), cyclic adenosine diphosphate ribose (cADPR) and nicotinamide. CD38 can also degrade NAD precursors and NADP^{[9, 10]}. However, the function and role of CD38 in cochlea have not been reported.

Apigenin is a flavonoid with 4, 5, and 7-trihydroxyflavone which has been found in vegetables (parsley, celery), fruits, and tea^[11]. Studies have shown that Apigenin can increase NAD + levels by inhibiting CD38.Therefore apigenin can be used to regulate NAD/NADH and treat metabolic syndrome^[12] and reduce mitochondrial oxidative stress ^[13]. We speculated that Apigenin may inhibit the expression of CD38 in the cochlea during noise induced hearing loss. So far, there is no report on using the Apigenin in NIHL.

The purpose of this study is to explore cochlear inflammation in NIHL and if Apigenin can be used as a therapeutic agent in the inner ear protection during noise exposure.

Animals

Healthy C57/BL6J mice (6–8 weeks, male, weighing 18 ~ 22g) were purchased from SPF (Beijing) biotechnology company. All of the mice went through an auditory brainstem response (ABR) test to ensure normal hearing. The animals were divided into control group, noise exposure group and noise + Apigenen group by using a random number table.TDT system and Biosig software (TDT, USA) were used for ABR testing. This study was approved by the Institutional Animal Care and Use Committee of Chinese PLA General Hospital.

Noise exposure

The animals in the noise exposure group, the NE + Ana group and the NE + Api group were placed in the mesh cases and were subjected to 4 hours white noise at 120 dB SPL on 2 consecutive days. The noise signal was routed to loudspeaker (Aijie Audio Equipment Factory) through a power amplifier (MF-1201 MOSTET, ATech). The intensity of the sound field was calibrated using a sound level meter ((Brüel & Kjær, 2250L, Denmark) during the exposure. The control group did not receive noise exposure. This noise exposure method was proved to give rise to 30 ~ 50 dB threshold shifts.

Cochlear tissue preparation

The animals were sacrificed by spinal dislocation under anesthesia with pentobarbital sodium (0.8mg/kg) after experiment. Both sides of the cochlear were dissected and placed in a cool PBS solution for further studies.

The basilar membrane tissue of the control group and noise exposure group was extracted using a protein extraction kit (bangfei bioscience), then capsuled in EP tubes marked Ctrl 1, Ctrl 2, Ctrl3 (control group) and NE1, NE2, NE3(noise exposure group). Each tube contains membrane tissues collected from 30 mice. The actual protein concentration was quantified by microplate reader. The tissue of each group was catalyzed by trypsin (Promega, V5113) for 16h, then the peptide was labeled according to the TMT kit instructions. Each sample was separated by HPLC (high-performance liquid chromatography) liquid phase system at a nanoliter flow rate, and then loaded into mass spectrometry precolumn and the analytical column. A total of 6 samples were pooled dissolved respectively in 2% acetonitrile solution and loaded onto the reverse-phase column. Then eluted the sample with 98% acetonitrile solution using a step linear elution program at a rate of 0.7 ml/min for 30 min. The samples were collected every 1.5 min during the elution procedure[14].

Bioinformatics Analysis

According to the protein quantitative results of the samples, protein difference was screened out between the NE group and the control group (student-T test, P < 0.05). Proteins with FC (fold change) ≥ 1.2 and P < 0.05 were defined as up-regulated, and proteins with FC ≤ 0.833 and P < 0.05 were defined as down-regulated. The differential proteins were compared with all protein backgrounds by searching the online database (http://www.geneontology.org), and the biological functions related to the differential proteins were inferred according to the significantly enriched GO functional items in the differential proteins. Firstly, all differential proteins were mapped to each item in the Gene Ontology database, and the number of proteins contained in each item was calculated based on the hypergeometric distribution.

Immunofluorescence

The cochlear basilar membrane was prepared with the surface preparation method, antibodies used in this experiment were rabbit anti-NF-κB p65 polyclonal antibody (Abcam, ab32536), rat anti-F4/80 polyclonal antibody (Abcam, ab6640), mouse anti-CD38 polyclonal antibody. Rinse thoroughly and seal the tablet with DAPI-containing glycerin (Abcam, ab228549). The specimens were observed by excitation light at 405nm (blue), 488nm (green) and 555nm (red) with a Zeise confocal microscope. The specimens were scanned with a thickness of 0.26µm. The images were superimposed by orthogonal projection using ZEN (Blue 2.3SP) software.

Western blot

Western blot was performed to quantitatively analyze CD38 and NF-κB expression in the cochlear of each group. Animals were sacrificed 7 days after noise exposure, and the whole cochlear protein was extracted. After polyacrylamide gel electrophoresis, membrane transfer and 5% skim milk powder sealing, Primary antibodies were incubated at 4℃ overnight. The next day, corresponding secondary antibodies were treated at room temperature for 1 hour. The primary antibody used in this study were anti-CD38 (Abcam, ab216343), anti-NF- kappaB (p65) (Abcam, ab32536) and anti-β-actin (Immunoway, YM3028). The protein band was visualized in darkroom on photographic film. Image J software was used to measure the gray value of the band, and the gray value ratio of the target protein to the internal reference protein was used as the relative content for statistical analysis.

Statistical analysis

SPSS 21.0 software was used for statistical analysis. Data were expressed as mean ± standard deviation. Student-T test was performed for comparison between the NE group and the control group. One-way ANOVA and Turkey test were performed for comparison of multiple group results. P < 0.05 was considered to be statistically significant.

Tandem Mass Tags (TMT) experiment result

A total of 12003 kinds of peptides and 3124 kinds of proteins were identified in this TMT experiment. The protein molecular weight is mainly concentrated in 10-120kDa (Fig. 1A).

A total of 131 differential proteins were screened out from the two groups, including 37 up-regulated proteins and 94 down-regulated proteins. The frequency histogram is drawn by the screening results. Statistical analysis was conducted on the screened significantly different proteins and a volcano map was drawn. The abscissa was the logarithm of log10 of the multiple differences of proteins between the two groups, and the ordinate was the logarithm of log10 of the P value. As shown in Fig. 1, the black dots represent proteins with no significant change in the NE group compared with the control group, the red dots represent up-regulated proteins in the NE group, and the green dots represent down-regulated proteins in the NE group.

GO analysis showed that the differential proteins were mainly enriched in metabolic processes, including NAD/NADP + activity, norepinephrine metabolic process, and negative regulation of inflammatory response to antigenic stimuli regulation of inflammation to an antigenic stimulus, glutathione derivative metabolic retinoid metabolic process, retinoid metabolic process.

In order to find the reason for the decrease of NAD level in cochlear, we verified NAD hydrolase CD38 took part in the inflammatory process.

The activation of NF-κB signal pathway has been shown to mediate noise-induced cochlear inflammation. It has been reported that NF-κB can promote the transcription of CD38 gene^[15]. We observed NF-κB expression and nuclear transfer after noise exposure by immunofluorescence staining. Through immunofluorescence co-staining of CD38 and F4/80 antibodies, we found basilar membrane macrophages were the main source of CD38 expression, which mainly existed in scala tympani. As the closest immune cell to organ of Corti, activated macrophages express CD38 and consume NAD in organ of Corti, causing dysfunction of hair cell metabolism, inflammasome and caspase expression and ultimately leads to hair cell apoptosis. In this process, inflammatory factors such as TNF-α, IL-1 and IL-6 promoted the activation of NF-κB signal pathway, forming the cycle.

Then the experimental group of mice were treated with IL-1 blocker Anakinra and CD38 inhibitor Apigenin. After the administration of Anakinra, the difference of the ABR thresholds between the NE + Ana group and the NE group were not obvious. 14 days after noise exposure, the ABR threshold of the NE group were 45.7 ± 12.9 dB SPL, 45.7 ± 7.3 dB SPL, 60.7 ± 7.8 dB SPL, 73.6 ± 3.5 dB SPL, 79.3 ± 1.7 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz, while the ABR threshold of the NE + Ana group were 37.5 ± 6.6 dB SPL, 43.8 ± 11.9 dB SPL, 62.5 ± 8.5 dB SPL, 67.1 ± 5.9 dB SPL, 76.7 ± 4.7 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz (Fig. 7, n = 5).

After being given Apigenin, multiple frequency hearing thresholds were significantly reduced compared with the NE group 7 days after the noise. 7 days after noise exposure, the ABR threshold of the NE group were 55.7 ± 17.3 dB SPL, 57.5 ± 16 dB SPL, 61.1 ± 14.4 dB SPL, 74.6 ± 5.5 dB SPL, 79.3 ± 1.7 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz, while the ABR threshold of the NE + Api group were 43.6 ± 10.4 dB SPL, 43.6 ± 11.1 dB SPL, 48 ± 13.4 dB SPL, 68.57 ± 7.4 dB SPL, 77.1 ± 4.1 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz. 14 days after noise exposure, the ABR threshold of the NE group were 55.7 ± 13.5 dB SPL, 56.1 ± 13 dB SPL, 60.4 ± 18.8 dB SPL, 76.4 ± 5.5 dB SPL, 79.6 ± 1.3 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz, while the ABR threshold of the NE + Api group were 42.1 ± 9 dB SPL, 42.9 ± 10.3 dB SPL, 43.2 ± 13.0 dB SPL, 71.8 ± 8.6 dB SPL, 79.3 ± 1.7 dB SPL at click, 4k Hz, 8k Hz 16k Hz and 24k Hz (Fig. 8, n = 7).

In order to explore the effect of Apigenin on the expression of CD38, we extracted two groups of cochlear protein at 7 days after noise to conduct Western blot experiment, including NF-κB(p65) and CD38 protein. It was found that compared with the control group, the expression of NF-κB(p65) and CD38 protein after noise exposure was significantly increased, and the increase in the NE group was most significant (P < 0.01). The protein band showed that NF-κB(p65) in the NE + Ana group was significantly lower than that in the NE group(P < 0.05), while the CD38 expression was not affected. After Apigenin, NF-κB and CD38 expression were significantly decreased compared with the NE group(P < 0.01).

On the 14th day after noise exposure, the cochlear of the NE group and the NE + Api group were taken by scanning electron microscopy. It was found that the cilium of the outer hair cells in the NE group was severely damaged, most of which collapsed or even disappeared. Outer hair cell cilium of the NE + Api group was slightly scattered and rarely disappeared (Fig. 10).

TMT technology is an innovative vitro peptide tagging technology, which has been applied to study various disease mechanisms^[16]. In this study, 3124 proteins of mouse basilar membrane were identified by TMT experiment, and 131 proteins were significantly differentially expressed after noise exposure, including 37 up-regulated proteins and 94 down-regulated proteins. GO enrichment analysis was used to detect changes in various metabolic reactions after noise exposure. We found that noise exposure may induce NAD metabolic disorder, which would cause cell damage and inflammatory responses by affecting cellular respiration.

As reported, NAD decrease affects the cell respiration process, resulting in damage to DNA and mitochondria^[17]. NAD acts as co-factors in the Krebs cycle and cell respiration^[18], therefore NAD is considered related to various diseases such as aging, neurological disorders and cancer^[19].

Haemophilus mediates a variety of infection processes. Because it lacks the ability to synthesize NAD, it can only meet its physiological activities and metabolism by ingesting NAD and NAD in the environment^[20]. CD38-positive immune cells could consume NAD in the environment, and therefore confining infection. It seemed that similar signaling pathways promote the activation of macrophages during inflammation of the inner ear, causing damage to the inner ear.

Cochlear used to be considered an "immune-free" organ due to the exit of blood-labyrinth barrier(BBB)^[21]. Recent years, noise exposure has been observed to induce cochlear immune cell recruitment, immune response and expression of inflammatory factors. NF-κB signal pathway is involved in the inflammation of innate and acquired immunity^{[22, 23]}. Generally, the nuclear transcription factor Kappa B(NF-κB) exists with the form of p50-P65 dimer binding to kappa B inhibitor protein, which activates and promotes the expression of multiple genes when cells received stimulant signals. NF-κB nuclear translocation is related to cochlear inflammatory reactions^[24], and leads to apoptosis and necrosis of hair cells^[25]. NF-κB signal passway is closely related to the gene expression of inflammatory factors. After noise exposure, NF-κB signal pathway regulate inflammasome NLRP3 to promote the transcription of various inflammatory factors, and activate cysteine aspartate proteases mediated apoptosis, such as caspase-1 and caspase-3^[26]. The accompanying IL-6, TNF-α and IL-1β have been proven to be important factors involved in regulating the onset and progression of noise-induced cochlear inflammation^[27].

CD38 is also a downstream part of NF-κB signal pathway, and is believed to be involved in neurodegenerative diseases^[28]. We labeled macrophages with F4/80 antibody^[29] and co-stained with CD38 antibody, and the expression of CD38 was quantified by Western blot. The number of macrophages in the basilar membrane was significantly higher than that in the control group 7 days after noise exposure (P < 0.05), suggesting that macrophages infiltrate the basilar membrane and mediate inflammatory response after noise exposure. CD38 was observed to be expressed on the surface of macrophages after noise exposure. Western blot quantification of cochlear protein showed that CD38 protein in the NE group was significantly higher than that in the control group (P < 0.05). This suggests that activation and expression of CD38 by macrophages may be the cause of basilar membrane macrophage infiltration and NAD consumption^[30].

We also tested the protective effects of Anakinra and Apigenin to reduce the ABR threshold shift by inhibiting cochlear inflammation. Clinically, Anakinra has been found that the NLRP3 gene mutation and has been tested in a clinic study^[32]. Recent clinical studies have shown that Anakinra can reduce the inflammatory response of COVID-19 patients and improve the survival rate without mechanical ventilation^[33]. As a downstream blocker in this signal pathway, Anakinra showed limited effects on hearing protection. We suggest the protective effect of Apigenin depends on both the noise intensity and the duration of medication administration. It is known high frequency hearing is more vulnerable to noise exposure, Apigenin showed an obvious protective effect on 4k Hz and 8k Hz frequency ABR thresholds 7 days after noise exposure, thus inflammation may not be the primary cause of hair cell damage in the basal turn. Western blot showed that Anakinra also inhibited NF-κB expression after noise exposure. However, we found that NF-κB (P65) expression was significantly increased in the NE + Ana group compared with the control group. The Cilium of outer cochlear hair cells can be effectively protected by Apigenin, which can reduce the threshold shift by about 20dB. Western blot showed that Apigenin inhibited the expression of CD38 protein in cochlear after noise exposure, and down-regulated the expression of NF-κB signal pathway. It seemed that blocking IL-1β, one of several factors involved in NF-κB activation, cannot block NF-κB activation completely. This may also be the reason why Anakinra did not show a significant effect on the first 7 days of administration.

Apigenin can increase the level of NAD + in vivo by inhibiting CD38, thereby treating metabolic syndrome^[12], and reduce the level of mitochondrial oxidative stress by regulating NAD/NADH ratio and Sirt3 activity^[13]. As shown in the result, the ABR threshold of NE + Api group was significantly lower than that of the NE group, with significant differences at CLICK (P < 0.05), 4kHz (P < 0.05) and 8kHz (P < 0.05) 7 days after noise exposure. Scanning electron microscopy proved that Apigenin has an obvious protective effect on hair cell cilia.

In summary, the TMT experiment provided a wide perspective to understand the physiological and pathological processes in cochlear. Based on proteomic analysis results, this study discussed the role of NF-κB pathway and CD38 expression in cochlear inflammation after noise exposure. We hypothesize that NF-κB activates basilar membrane macrophages to express CD38, leading to cochlear inflammation and hearing loss. The results of this study a provide reference for the CD38 in cochlear acoustic injury and its relationship with the inflammatory response. Inhibition of NF-κB and CD38 expression may be a new therapeutic strategy for noise-induced hearing loss.

Conflicts of Interest

The authors declare no conflicts of interest.

Ethics approval

The study method was approved by PLA General Hospital ethical committees.
Consent to participate

Informed consent was obtained from all individual participants included in the study.
Consent for publication

All Authors agreed with the final version of the manuscript.

Availability of data and materials

The data that support the findings of the study are not publicly available but are available from the corresponding authors.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC #81970897, #82000981), and Spring City Plan: the High-level Talent Promotion and Training Project of Kunming（2022SCP001）
Authors' contributions

Da Liu, Na Sai, Ying Zhou contributed equally to designing the work, data collection and data analysis. Weiwei Guo and Weiju Han were involving in critical reading of the article, drafting the article and final approval of the version of the article. Ning Yu, Qing-qing Jiang and Wei Sun were involving in critical reading, drafting the article and critical reading.
Acknowledgments

None

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CD38 coordinates with NF-κB to promote cochlear inflammation in noise-induced hearing loss：the protective effect of Apigenin

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