SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

Shen, Jian; Lai, Wenjia; Li, Zeyang; Zhu, Wenyuan; Bai, Xue; Yang, Zihao; Wang, Qingsong; Ji, Jianguo

doi:10.1007/s00011-024-01913-5

SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

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Published: 15 July 2024

(2024)
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SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

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Jian Shen¹^na1,
Wenjia Lai³^na1,
Zeyang Li²,
Wenyuan Zhu²,
Xue Bai²,
Zihao Yang²,
Qingsong Wang² &
…
Jianguo Ji²

Abstract

Background

Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear.

Methods

To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays.

Results

Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation.

Conclusions

Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.

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Introduction

Neurodegenerative diseases (NDs) are characterized by progressive neuron loss, resulting in severe motor impairments, cognitive decline, and dementia. The global incidence of NDs exceeds 40 million individuals and is strongly associated with advanced age [1]. The most common NDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis. Shared pathological features include neuronal dysfunction, aberrant protein aggregation, oxidative stress, programmed cell death, and neuroinflammation [2]. The molecular mechanisms underlying ND pathogenesis remain unclear, limiting therapeutic options for symptomatic relief. Consequently, understanding these mechanisms is crucial for the development of effective treatments.

Neuroinflammation is the central nervous system’s response to homeostatic imbalance and involves numerous cell types, such as microglia, astrocytes, and oligodendrocytes, the blood–brain barrier, cytokines, and cytokine signaling pathways [3]. Depending on the specific context triggering the inflammatory response, neuroinflammation can have either beneficial or detrimental effects. AD and PD are characterized by microglial and astrocytic activation and elevated levels of inflammatory mediators [4]. Genetic studies have also highlighted the association between inflammation-regulating genes and NDs [5,6,7,8,9,10], emphasizing the important role of neuroinflammation in disease pathogenesis.

Microglia, as the primary innate immune cells in the central nervous system, are essential for brain development, the maintenance of homeostasis, and response to infections. Under pathological conditions associated with aging and NDs, microglia undergo excessive activation and functional dysregulation, resulting in impaired degradation, heightened inflammatory responses, production of proinflammatory cytokines [11, 12], generation of reactive oxygen species [13, 14], and neurotoxicity, thereby exacerbating ND pathologies [15, 16]. Investigating the regulatory mechanisms of microglial inflammatory responses is crucial for a deeper understanding of ND pathogenesis.

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from acetylated lysine residues on histone and nonhistone proteins. HDAC1/2 can form four classical transcriptional co-repressor complexes, and the Sin3/HDAC complex is one of the classical multiprotein complexes formed by HDAC1/2 [17]. In mammalian cells, the core components of the Sin3/HDAC complex include paired amphipathic helix protein Sin3A/B (Sin3A/B), HDAC1/2, the Sin3 histone deacetylase corepressor complex component SDS3 (SDS3), retinoblastoma-binding protein 4/7 (RBBP4/7), 30-kDa Sin3-associated polypeptide (SAP30), and 18-kDa Sin3-associated polypeptide (SAP18). The Sin3/HDAC complex plays a critical role in processes such as the cell cycle, cell proliferation, and cellular senescence [18, 19]. The classical view is that Sin3/HDAC represses transcription through histone deacetylase activity and is therefore referred to as a transcriptional co-repressor complex [20, 21].

Some existing studies have revealed the regulatory role of Sin3/HDAC in inflammatory responses. In ovarian clear cell carcinoma cells with PIK3CA mutations, knockdown of ARID1A impedes recruitment of the Sin3A/HDAC complex to the promoters of cytokines genes, such as IL6 and IL8, releasing transcriptional repression and promoting cytokine production and cancer progression [22]. In mouse macrophages, lipopolysaccharide (LPS) treatment induces recruitment of the Sin3A/HDAC complex to the promoter region of the gene encoding inducible nitric oxide synthase (iNOS), thereby inhibiting iNOS expression [23]. In human macrophages, the Sin3A/HDAC complex can bind to the promoter regions of interferon (IFN) response genes, such as IFNB1 and IRF7, as well as proinflammatory genes, such as TNFS and CCL3. After LPS treatment, the binding of Sin3A to these promoter regions is reduced, resulting in upregulated gene expression [24]. Together, these studies suggest that the Sin3/HDAC complex negatively regulates inflammatory responses through transcriptional repression in different contexts.

SDS3 is one of the core components of the Sin3/HDAC complex and plays a critical role in maintaining the integrity and histone deacetylase activity of the complex [25, Full size table

ChIP-seq identified SDS3 target genes, and siSDS3_DEP were labeled on the GO enrichment analysis results of siSDS3_DEG (Fig. 3C). Genes that were increased in expression that were related to neuroinflammation, including Ptgs2 (also known as COX-2, prostaglandin G/H synthase 2) and Tlr6 (Toll-like receptor 6), as well as the downregulated gene Ffar4 (free fatty acid receptor 4) are all SDS3 target genes. Among them, COX-2 and Tlr6 were transcriptionally inhibited by SDS3. IL-1β and iNOS were not identified as SDS3 target genes, suggesting that their regulation by SDS3 may be indirect. Our proteomic results showed that the change in COX-2 protein expression due to SDS3 knockout (COX-2 ratio of 1.2) did not reach statistical significance. Similarly, in untreated BV2 cells, due to the low basal expression level of COX-2, no significant changes in COX-2 expression were observed between BV2^ctrl and BV2^{SDS3 − KD} cells (Fig. 1F and G). However, after LPS induction, COX-2 expression changed significantly, suggesting that the expression of COX-2 is regulated not only by SDS3 through negative regulation but also by other regulatory mechanisms.

Further analysis of the data in Fig. 3C revealed that SDS3 downstream genes, including Map3k5, Met, and Xdh, are involved in the regulation of the p38 MAPK signaling cascade. The corresponding protein levels of mitogen-activated protein kinase kinase kinase 5 (MAP3K5) and xanthine dehydrogenase/oxidase (XDH) were also significantly upregulated (Table 1; Fig. 3B). The p38 MAPK signaling pathway can be activated by various stimuli, both inside and outside the cell, and it is a key signaling pathway involved in the regulation of inflammatory responses [34, 35]. XDH plays a critical role in purine degradation and can influence cell activity by regulating the production of reactive oxygen species [36]. MAP3K5, also known as apoptosis signal-regulating kinase 1 (ASK1), is one of the upstream kinases of p38 MAPK. ASK1 can be activated by a range of intracellular and extracellular stimuli and, through signal transduction, activates the downstream p38 MAPK signaling pathway. SDS3 may regulate the expression of genes related to the p38 MAPK signaling pathway and thereby modulate inflammatory responses.

SDS3 regulates the activation of p38 MAPK

Activation of p38 MAPK can be assessed by the phosphorylation of Thr180 and Tyr182 (referred to as p-p38). In BV2 cells, SDS3 knockdown was performed, and changes in p-p38 before and after LPS treatment were examined. In the absence of LPS treatment, SDS3 knockdown led to an upregulation in p-p38 compared with that observed in the control group (Control siRNA). After LPS treatment, there was a significant increase in p-p38 in microglia, and SDS3 knockdown further enhanced this process, resulting in the highest level of p-p38. This suggests that SDS3 knockdown promotes activation of the p38 MAPK pathway in microglia.

SB203580 is an inhibitor of p38 MAPK kinase activity that negatively regulates the p38 MAPK signaling pathway and its downstream effects. We treated BV2 cells with SB203580 or DMSO followed by LPS and assessed the expression of inflammatory factors by Western blotting. Inhibiting p38 MAPK activity resulted in decreased expression of LPS-induced inflammatory factors (Fig. 4B and Supplemental Fig. S4A, quantitative bar graph), indicating that the p38 MAPK signaling pathway can regulate the LPS-induced inflammatory response in microglia.

SDS3 regulates the expression of ASK1

To validate the transcriptional regulation of ASK1 by SDS3, three primer pairs were designed in the ASK1 promoter approximately 0, 500, and 800 bp upstream of the first exon. ChIP experiments were then conducted in BV2 cells using anti-SDS3 or IgG control antibody to enrich DNA fragments bound by SDS3 and assess the DNA content of the ASK1 promoter by qPCR, thereby determining the ability of SDS3 to bind the ASK1 promoter. Pulldown with anti-SDS3 demonstrated enrichment of the ASK1 promoter region compared with pulldown with IgG control (Fig. 5A), indicating that SDS3 can bind to the ASK1 promoter. SDS3 knockdown was then performed in BV2 cells, and the expression of ASK1 was examined. Consistent with the proteomic and RNA-seq results, SDS3 knockdown resulted in a significant upregulation in ASK1 expression (Fig. 5B), indicating that SDS3 knockdown can enhance the expression of ASK1 in microglia, thus confirming ASK1 as a downstream gene that is negatively regulated by SDS3.

In addition, SDS3 forms a complex with HDAC1 in microglia (Fig. 1A), and ChIP-qPCR experiments showed that the ASK1 promoter region is enriched following pulldown with anti-HDAC1 (Fig. 5C). Similarly, knockdown of HDAC1 in BV2 cells also increased ASK1 expression (Fig. 5D). These results suggest that HDAC1 also binds to the ASK1 promoter region, indicating that SDS3 may inhibit the expression of ASK1 by forming the Sin3/HDAC transcriptional co-repressor complex.

ASK1 regulates microglial inflammatory processes through the p38 MAPK signaling pathway

ASK1, as an upstream kinase of the p38 MAPK, plays a crucial role in regulating the inflammatory response in microglia. To investigate the role of ASK1 in inflammation, ASK1 was knocked out using CRISPR-Cas9 technology in BV2 cells (BV2^{ASK1 − KO}; Fig. 6A). Compared with normal cells (BV2^WT), p-p38 was significantly decreased in BV2^{ASK1 − KO} cells (Fig. 6B). After LPS stimulation, p-p38 levels were significantly increased in both cell groups; however, p-p38 was lower in BV2^{ASK1 − KO} cells than in BV2^WT cells (Fig. 6B). Following LPS stimulation, the expression of iNOS, COX-2, and IL-1β was significantly upregulated in both BV2^WT and BV2^{ASK1 − KO} cells compared with untreated cells; however, expression in BV2^{ASK1 − KO} cells was lower than in BV2^WT cells (Fig. 6C and D and Supplemental Fig. S4B, quantitative bar graph). Accordingly, BV2^WT and BV2^{ASK1 − KO} cells exhibited an increase in nitric oxide production after LPS treatment; however, nitric oxide production in BV2^{ASK1 − KO} cells was lower than in BV2^WT cells (Fig. 6E). Together, these results suggest that knocking out ASK1 can partially inhibit activation of p38 MAPK induced by LPS, thereby reducing the expression of the inflammatory factors iNOS, COX2, and IL-1β and inhibiting nitric oxide production in microglia.

ASK1 knockout affects the regulation of SDS3 and the inflammatory response

LPS stimulation downregulates SDS3 expression (Fig. 1), and knockdown of SDS3 can upregulate the expression of LPS-induced inflammatory factors (Fig. 2). To investigate whether ASK1 knockout affects the regulation of SDS3 and the expression of inflammatory factors, BV2^{ASK1 − KO} and BV2^WT cells were transfected with SDS3 siRNA (SDS3-KD) or Control siRNA (ctrl). After 6 h of LPS treatment, compared with the control group (BV2^{WT + ctrl}), the expression of SDS3 was significantly downregulated in BV2^{WT + SDS3−KD} cells, indicating successful knockdown of SDS3 expression (Fig. 7A and B). Moreover, the expression of COX-2 and IL-1β was significantly upregulated in BV2^{WT + SDS3−KD} cells compared to in BV2^{WT + ctrl} cells, indicating that knocking down SDS3 significantly increases the expression of COX-2 and IL-1β in BV2^{WT + SDS3−KD} cells (Fig. 7A and B). In BV2^{ASK1 − KO} cells, after LPS treatment, SDS3 expression was similarly decreased in BV2^{ASK1 − KO + SDS3−KD} and BV2^{ASK1 − KO + ctrl} cells. However, because of a lack of ASK1 in these cells, there were no significant changes in the expression of COX-2 and IL-1β between BV2^{ASK1 − KO + SDS3−KD} and BV2^{ASK1 − KO + ctrl} cells even after LPS stimulation (Fig. 7A and B and Supplemental Fig. S4C, quantitative bar graph). These results indicate that knocking out ASK1 affects the regulation of SDS3 on the expression of inflammatory mediators. Additionally, the regulation of microglial inflammation by SDS3, to some extent, depends on its inhibition of the downstream gene ASK1.

Discussion

LPS is a major component of the outer membrane of Gram-negative bacteria and is one of the most extensively studied ligands for TLR4, a typical pattern recognition receptor involved in initiating infectious and noninfectious inflammatory responses [37, 38]. TLR4 is expressed in neurons and glia in the central nervous system, with the highest expression levels observed in microglia [16, 39]. LPS can activate microglia, leading to the production of proinflammatory cytokines and inflammatory mediators, such as nitric oxide, which can cause neuronal dysfunction and death [40, 41]. Therefore, LPS is widely used in molecular studies investigating microglial activation and neuroinflammation related to neurodegeneration [31, 42, 43].

In this study, we validated that SDS3 interacts with Sin3A and HDAC1 proteins in microglia (Fig. 1A) and found that the expression of SDS3 was decreased after LPS stimulation, and this decrease was not the result of proteasomal degradation (Fig. 1B–E). Other components of the Sin3/HDAC complex did change in expression. Contradictory data exist regarding the role of HDAC1/2 in inflammation [44,45,46,47]. This may be due to the lack of specificity of the HDAC inhibitors used, which cannot precisely regulate the activity of HDAC1/2. Alternatively, HDAC1/2 can form various complexes and exert complex regulatory functions. Similarly, Sin3A, as a scaffold protein of the complex, participates in the formation of the Sin3/HDAC complex and also interacts with various components of histone modification complexes and transcription factors, exhibiting complex gene regulatory functions [48]. As SDS3 is a regulatory subunit of the Sin3/HDAC complex, it can mediate the simultaneous deacetylation of distantly located nucleosomes by forming dimers and increase the chromatin anchoring ability of the complex by binding to DNA, which is necessary for the integrity and catalytic activity of the Sin3/HDAC complex [26]. SDS3 may act as a “switch” molecule, mediating flexible regulation of the recruitment sites and catalytic activity of the complex. Previous reports have shown that the expression of regulatory subunits can modulate the function of histone modification complexes [49]. Compared with Sin3A and HDAC1, SDS3 has a simpler and more specific molecular interaction in the complex. Therefore, interfering with SDS3 to explore the function of the Sin3/HDAC complex in the inflammatory response is more specific and straightforward.

In macrophages, the Sin3A/HDAC complex can inhibit the expression of proinflammatory genes by binding to their promoter regions, thus suppressing the inflammatory response [23, 24]. Here, we demonstrated that knocking down SDS3 in BV2 cells can promote the expression of LPS-induced inflammatory factors (iNOS, COX-2, and IL-1β) and the release of nitric oxide (Fig. 1F-H). By integrating transcriptomic and proteomic data and conducting bioinformatic analyses, we explored changes in mRNA and protein profiles in SDS3-knockdown microglia. Based on a clustering analysis of differentially expressed genes and proteins, we hypothesized that SDS3 is involved in regulating biological processes related to microglial inflammation (Fig. 2C and E), and our results support this hypothesis. ChIP-seq analysis combined with transcriptomics identified genes potentially regulated by SDS3 (Supplemental Table S8). Analysis of the biological pathways in which these downstream genes are involved revealed the participation of SDS3-regulated genes in the p38 MAPK signaling pathway (Fig. 3C). Subsequent experiments in BV2 cells showed that knocking down SDS3 can upregulate p-p38, suggesting activation of the p38 MAPK signaling pathway. LPS stimulation increased p-p38 in BV2 cells, and knocking down SDS3 further enhanced this phosphorylation (Fig. 4A), confirming the negative regulation of SDS3 on the p38 MAPK signaling pathway. These findings indicate that SDS3 plays an important role in regulating the inflammatory response through modulation of the p38 MAPK signaling pathway.

MAPKs are a group of serine and threonine kinases that can translate extracellular stimuli into a series of intracellular responses. Activated p38 MAPK can phosphorylate a range of nuclear and cytoplasmic proteins primarily involved in gene transcription regulation [50, 51]. The p38 MAPK signaling pathway is rapidly activated in response to various stress conditions, such as oxidative stress, osmotic stress, endoplasmic reticulum stress, and inflammatory stimuli, and it regulates cellular processes to adapt to these stimuli [52]. Inhibiting p38 activity reduces the production of IL-8 under osmotic stress [53] and IL-6 under TNFα stimulation [54]. In addition, inhibiting p38 activity hinders the expression of COX-2 in macrophages stimulated by LPS [55], and in p38-deficient macrophages, the production of TNFα, IL-12, and IL-18 induced by LPS is reduced [56], indicating that inhibiting p38 MAPK activity can decrease the production of inflammatory factors. In microglia, LPS can activate the p38 MAPK signaling pathway and promote the production of TNFα, IL-1β, and nitric oxide [57, 58]. Additionally, the Aβ25–35 fragment activates the p38 MAPK signaling pathway and induces the generation of IL-1β and nitric oxide in microglia, whereas fibrillar Aβ1–42 induces the production of TNFα and IL-1β through the p38 MAPK pathway [59]. Following ischemic brain injury, disruption of the blood–brain barrier and neuronal cell death lead to the exposure to substances in blood vessels and within brain cells, which can activate microglia and trigger p38 MAPK pathway activation, leading to the production of inflammatory factors [60,61,62]. Therefore, under pathological conditions, such as ND and brain injury, activation of the p38 MAPK signaling pathway in microglia promotes neuroinflammation and exacerbates disease progression. Our experiments also confirmed that inhibiting p38 MAPK activity in BV2 cells decreases the expression of LPS-induced inflammatory factors (Fig. 4B), validating the regulatory role of the p38 MAPK pathway in the inflammatory response.

Our analysis revealed that ASK1 and XDH, the downstream genes of SDS3, are involved in regulating the p38 MAPK signaling pathway. We observed that the expression of ASK1 and XDH was upregulated in BV2^{SDS3 − KD} cells (Fig. 3B; Table 1). ASK1 is a MAP3K protein that directly phosphorylates MKK3/MKK6, which are specific MAP2Ks of the p38 MAPK family. MKK3/MKK6, in turn, directly phosphorylate the threonine and tyrosine residues of the Thr-Gly-Tyr motif, activating the downstream p38 signaling pathway and participating in the regulation of inflammatory responses under various stimuli [63, 64]. The kinase activity and abundance of ASK1 are regulated by multiple mechanisms, with previous studies primarily focusing on post-translational modifications and protein degradation [65,66,67,68,69]. Less is known about the regulatory mechanisms of ASK1 expression. Among the known proteins that regulate ASK1 expression, E2F1, KLF5, and HNF4α promote expression, whereas BRG1 inhibits it [66, 67, 70, 71]. Our ChIP-qPCR experiments demonstrated that both SDS3 and HDAC can bind to the ASK1 promoter, and knocking down SDS3 or HDAC can promote the expression of ASK1 (Fig. 5). This suggests that SDS3 inhibits the expression of ASK1 through the formation of transcriptional complexes in microglia. These findings reveal new proteins involved in the regulation of ASK1 expression.

ASK1 is involved in the activation of signaling pathways, including the NF-κB and MAPK signaling pathways, which are mediated by TLRs, and plays a role in the natural immune response, including inflammation. For example, in splenocytes and dendritic cells from ASK1-knockout mice stimulated with the TLR4 ligand LPS, the production of proinflammatory cytokines, such as TNFα, IL-6, and IL-1β, was reduced, and activation of the p38 MAPK pathway was inhibited [72]. Similarly, in 293T cells overexpressing the TLR2 receptor, activation of the p38 MAPK signaling pathway was observed after ligand stimulation, whereas overexpression of a dominant-negative form of ASK1 significantly inhibited activation of the p38 MAPK signaling pathway [73]. Consistently, macrophages overexpressing the dominant-negative form of ASK1 showed a significant reduction in TNFα and IL-6 production after TLR2 ligand stimulation [74, 75]. These studies suggest that ASK1 mediates inflammation through the p38 MAPK signaling pathway. Additionally, experiments in ASK1-knockout mice showed that ASK1 promotes inflammatory responses in diseases such as allergic asthma, rheumatoid arthritis, drug-induced liver injury, and contact hypersensitivity [76]. In microglia, ASK1 is involved in regulating cellular responses to various external stimuli. For example, microglia from ASK1-knockout mice showed reduced production of TNFα and iNOS after LPS stimulation [77]. In the brains of ASK1-deficient mice, decreased activation of microglia and reduced levels of TNFα, IL-6, and IL-1β were observed following brain ischemia. Similarly, knocking down ASK1 in BV2 cells led to a decrease in proinflammatory cytokine production induced by oxygen-glucose deprivation [78]. Stimulation with high glucose induced upregulation of ASK1 expression in BV2 cells, and inhibition of ASK1 activity resulted in decreased expression of TNFα and IL-6 induced by high glucose [79]. Furthermore, ASK1 promotes cobalt protoporphyrin-induced COX-2 expression in BV2 cells [80]. These studies collectively indicate that ASK1 is involved in promoting inflammatory responses in microglia after stimulation by various factors.

Our experiments revealed that knocking out ASK1 in BV2 cells leads to a decrease in p-p38 and inhibition of the expression of LPS-induced inflammatory factors (Fig. 6), indicating that ASK1 can mediate LPS-induced inflammatory responses through the regulation of the p38 MAPK signaling pathway, which is consistent with previous findings. In BV2 ASK1-knockout cells, knocking down SDS3 expression did not affect the expression of certain LPS-induced inflammatory factors (Fig. 7), further suggesting that ASK1 is a necessary downstream protein for the inflammatory regulatory role of SDS3.

In summary, we discovered that LPS stimulation downregulates the expression of the transcriptional co-repressor SDS3 in microglia, and SDS3 regulates the activation of the p38 MAPK signaling pathway through the modulation of the upstream kinase ASK1, thereby modulating LPS-induced inflammatory responses in microglia (Fig. 7C). It is worth noting that SDS3 does not possess specific DNA-binding activity, and its recruitment to the genome depends on sequence-specific transcription factors such as FOXK1 [81]. Further studies are needed to investigate the specific transcription factors that can bind to the ASK1 promoter region and the involvement of other coacting histone-modifying enzymes in the regulation of ASK1 expression.

Conclusion

Neuroinflammation is a stress response in the central nervous system that helps maintain homeostasis. Excessive and persistent neuroinflammation leads to neuron death and contributes to the pathogenesis of various NDs. Microglia play a crucial role in maintaining central nervous system homeostasis. Excessive and sustained neuroinflammation mediated by microglia leads to neuron dysfunction and death, which is closely associated with the pathogenesis of various NDs. The Sin3/HDAC complex is a classic multiprotein complex in mammals that is primarily involved in transcriptional repression through its deacetylase activity. SDS3 is a core component of the Sin3/HDAC complex and is essential for maintaining complex integrity and deacetylase activity. Through a series of experiments and ‘omics analyses, we validated that downregulation of SDS3 can promote the expression of the upstream kinase ASK1, activate the p38 MAPK signaling pathway, and subsequently enhance LPS-induced inflammatory responses in microglia. We provide important evidence of the contributions of SDS3 toward microglial inflammation, thereby extending the inhibitory role of the Sin3/HDAC complex to inflammation in microglia. Importantly, our findings highlight the crucial role of SDS3 in this regulatory function and provide new insights into the biological function of SDS3 and the regulatory mechanisms of microglial inflammation.

Data availability

No datasets were generated or analysed during the current study.

References

Wood LB, Winslow AR, Strasser SD. Systems biology of neurodegenerative diseases. Integr Biol. 2015;7:758–75.
Article CAS Google Scholar
Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2017;9:a028035.
Article PubMed PubMed Central Google Scholar
Ransohoff RM, Schafer D, Vincent A, Blachère NE, Bar-Or A. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics. 2015;12:896–909.
Article CAS PubMed PubMed Central Google Scholar
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777–83.
Article CAS PubMed Google Scholar
Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41:1094.
Article CAS PubMed Google Scholar
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43:429.
Article CAS PubMed PubMed Central Google Scholar
Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43:436–41.
Article CAS PubMed PubMed Central Google Scholar
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16.
Article CAS PubMed Google Scholar
Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet. 2010;42:781.
Article CAS PubMed PubMed Central Google Scholar
Kauwe JSK, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL et al. Genome-wide association study of CSF levels of 59 alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet. 2014;10.
Daniele SG, Béraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci Signal. 2015;8:ra45–45.
Article PubMed PubMed Central Google Scholar
Kim C, Ho D-H, Suk J-E, You S, Michael S, Kang J, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4:1562.
Article PubMed Google Scholar
El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. CD36 mediates the innate host response to β-amyloid. J Exp Med. 2003;197:1657–66.
Article PubMed PubMed Central Google Scholar
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155–61.
Article CAS PubMed Google Scholar
Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.
Article CAS PubMed Google Scholar
Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med. 2018;69:437–49.
Article CAS PubMed Google Scholar
Millard CJ, Watson PJ, Fairall L, Schwabe JWR. Targeting class I histone deacetylases in a complex environment. Trends Pharmacol Sci. 2017;38:363–77.
Article CAS PubMed Google Scholar
Grandinetti KB, Jelinic P, DiMauro T, Pellegrino J, Fernandez Rodriguez R, Finnerty PM, et al. Sin3B expression is required for cellular senescence and is up-regulated upon oncogenic stress. Cancer Res. 2009;69:6430–7.
Article CAS PubMed PubMed Central Google Scholar
Dannenberg JH. mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival. Genes Dev. 2005;19:1581–95.
Article CAS PubMed PubMed Central Google Scholar
van Oevelen C, Wang J, Asp P, Yan Q, Kaelin WG, Kluger Y, et al. A role for mammalian Sin3 in permanent gene silencing. Mol Cell. 2008;32:359–70.
Article PubMed PubMed Central Google Scholar
Kadosh D, Struhl K. Targeted recruitment of the Sin3-Rpd3 histone deacetylase complex generates a highly localized domain of repressed chromatin in vivo. Mol Cell Biol. 1998;18:5121–7.
Article CAS PubMed PubMed Central Google Scholar
Kim M, Lu F, Zhang Y. Loss of HDAC-mediated repression and gain of NF-κB activation underlie cytokine induction in ARID1A-and PIK3CA-mutation-driven ovarian cancer. Cell Rep. 2016;17:275–88.
Article PubMed PubMed Central Google Scholar
Hwang S-Y, Hwang J-S, Kim S-Y, Han I-O. O-GlcNAc transferase inhibits LPS-mediated expression of inducible nitric oxide synthase through an increased interaction with mSin3A in RAW264. 7 cells. Am J Physiology-Cell Physiol. 2013;305:C601–8.
Article CAS Google Scholar
John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ, Song J, et al. IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages. Cell Rep. 2018;25:95–e1066.
Article CAS PubMed PubMed Central Google Scholar
Alland L, David G, Shen-Li H, Potes J, Muhle R, Lee HC, et al. Identification of mammalian Sds3 as an integral component of the Sin3/histone deacetylase corepressor complex. Mol Cell Biol. 2002;22:2743–50.
Article CAS PubMed PubMed Central Google Scholar
Clark MD, Marcum R, Graveline R, Chan CW, **e T, Chen Z, et al. Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex. PNAS. 2015;112:E3669–78.
Article CAS PubMed PubMed Central Google Scholar
Zhang K, Dai X, Wallingford MC, Mager J. Depletion of Suds3 reveals an essential role in early lineage specification. Dev Biol. 2013;373:359–72.
Article CAS PubMed Google Scholar
Lai W, Li D, Wang Q, Ma Y, Tian J, Fang Q. Bacterial magnetosomes release iron ions and induce regulation of iron homeostasis in endothelial cells. Nanomaterials (Basel, Switzerland). 2022;12.
Team RDC. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, Vienna, Austria,; 2010.
Google Scholar
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25:1091–3.
Article CAS PubMed PubMed Central Google Scholar
Nam HY, Nam JH, Yoon G, Lee J-Y, Nam Y, Kang H-J et al. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflamm. 2018;15.
Giustarini D, Rossi R, Milzani A, Dalle-Donne I. Nitrite and nitrate measurement by Griess reagent in human plasma: evaluation of interferences and standardization. Methods Enzymol. 2008;440:361–380. Elsevier.
Chen T-W, Li H-P, Lee C-C, Gan R-C, Huang P-J, Wu TH, et al. ChIPseek, a web-based analysis tool for ChIP data. BMC Genomics. 2014;15:539.
Article PubMed PubMed Central Google Scholar
Qi X-M, Chen G. p38γ MAPK inflammatory and metabolic signaling in physiology and disease. Cells. 2023;12:1674.
Wang J, Liu Y, Gu Y, Liu C, Yang Y, Fan X et al. Function and inhibition of P38 MAP kinase signaling: targeting multiple inflammation diseases. Biochem Pharmacol. 2023:115973.
Wang G, Qian P, Jackson FR, Qian G, Wu G. Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells. Int J Biochem Cell Biol. 2008;40:461–70.
Article CAS PubMed Google Scholar
Osborn MJ, Rosen SM, Rothfield L, Zeleznick LD, Horecker BL. Lipopolysaccharide of the Gram-negative cell wall. Science. 1964;145:783–9.
Article CAS PubMed Google Scholar
O’Neill LAJ, Golenbock D, Bowie AG. The history of toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13:453–60.
Article PubMed Google Scholar
Vaure Cl, Liu Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol. 2014; 5.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a toll-like receptor 4-dependent pathway. PNAS. 2003;100:8514–9.
Article CAS PubMed PubMed Central Google Scholar
Papageorgiou IE, Lewen A, Galow LV, Cesetti T, Scheffel J, Regen T, et al. TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ. PNAS. 2016;113:212–7.
Article CAS PubMed Google Scholar
Sheppard O, Coleman MP, Durrant CS. Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J Neuroinflamm. 2019;16:106.
Article Google Scholar
Martiskainen H, Paldanius KMA, Natunen T, Takalo M, Marttinen M, Leskelä S, et al. DHCR24 exerts neuroprotection upon inflammation-induced neuronal death. J Neuroinflamm. 2017;14:215.
Article Google Scholar
Guo X, Deng J, Zheng B, Liu H, Zhang Y, Ying Y et al. HDAC1 and HDAC2 regulate anti-inflammatory effects of anesthetic isoflurane in human monocytes. Immunol Cell Biol. 2020:imcb12318.
Durham BS, Grigg R, Wood IC. Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem. 2017;143:214–24.
Article CAS PubMed Google Scholar
Cantley MD, Fairlie DP, Bartold PM, Marino V, Gupta PK, Haynes DR. Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. Rheumatology. 2015;54:1713–23.
Article CAS PubMed Google Scholar
Kannan V, Brouwer N, Hanisch U-K, Regen T, Eggen BJL, Boddeke HWGM. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res. 2013;91:1133–42.
Article CAS PubMed Google Scholar
Kadamb R, Mittal S, Bansal N, Batra H, Saluja D. Sin3: insight into its transcription regulatory functions. Eur J Cell Biol. 2013;92:237–46.
Article CAS PubMed Google Scholar
Oksuz O, Narendra V, Lee C-H, Descostes N, LeRoy G, Raviram R, et al. Capturing the onset of PRC2-mediated repressive domain formation. Mol Cell. 2018;70:1149–e11625.
Article CAS PubMed PubMed Central Google Scholar
Arthur JSC. MSK activation and physiological roles. Front Biosci. 2008;5866.
Perdiguero E, Muñoz-Cánoves P. Transcriptional regulation by the p38 MAPK signaling pathway in mammalian cells. In: Posas F, Nebreda AR, editors. Stress-activated protein kinases. Volume 20. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008. pp. 51–79.
Chapter Google Scholar
Cuenda A, Rousseau S. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochimica et biophysica acta (BBA) -. Mol Cell Res. 2007;1773:1358–75.
CAS Google Scholar
Shapiro L, Dinarello CA. Osmotic regulation of cytokine synthesis in vitro. PNAS. 1995;92:12230–4.
Article CAS PubMed PubMed Central Google Scholar
Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, et al. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J. 1996;15:1914–23.
Article CAS PubMed PubMed Central Google Scholar
Hwang D, Jang BC, Yu G, Boudreau M. Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide. Biochem Pharmacol. 1997;54:87–96.
Article CAS PubMed Google Scholar
Kang YJ, Chen J, Otsuka M, Mols J, Ren S, Wang Y, et al. Macrophage deletion of p38α partially impairs lipopolysaccharide-induced cellular activation. J Immunol. 2008;180:5075–82.
Article CAS PubMed Google Scholar
Pyo H, Jou I, Jung S, Hong S, Joe E-h. Mitogen-activated protein kinases activated by lipopolysaccharide and β-amyloid in cultured rat microglia. NeuroReport. 1998;9:871–4.
Article CAS PubMed Google Scholar
Li Y, Liu L, Barger SW, Mrak RE, Griffin WST. Vitamin E suppression of microglial activation is neuroprotective. J Neurosci Res. 2001;66:163–70.
Article CAS PubMed PubMed Central Google Scholar
Combs CK, Karlo JC, Kao S-C, Landreth GE. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci. 2001;21:1179–88.
Article CAS PubMed PubMed Central Google Scholar
Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, et al. Extracellular ATP triggers tumor necrosis factor-α release from rat microglia. J Neurochem. 2000;75:965–72.
Article CAS PubMed Google Scholar
Ryu J, Pyo H, Jou I, Joe E. Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-κB. J Biol Chem. 2000;275:29955–9.
Article CAS PubMed Google Scholar
Tikka T, Fiebich BL, Goldsteins G, Keinänen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21:2580–8.
Article CAS PubMed PubMed Central Google Scholar
Chen Q, Guo J, Qiu T, Zhou J. Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: a critical pathway molecule worth investigating. J Gastroenterol Hepatol. 2023;38:378–85.
Article CAS PubMed Google Scholar
Ogier JM, Nayagam BA, Lockhart PJ. ASK1 inhibition: a therapeutic strategy with multi-system benefits. J Mol Med. 2020;98:335–48.
Article CAS PubMed Google Scholar
Chen M, Qu X, Zhang Z, Wu H, Qin X, Li F, et al. Cross-talk between arg methylation and ser phosphorylation modulates apoptosis signal–regulating kinase 1 activation in endothelial cells. MBoC. 2016;27:1358–66.
Article CAS PubMed PubMed Central Google Scholar
Hershko T, Korotayev K, Polager S, Ginsberg D. E2F1 modulates p38 MAPK phosphorylation via transcriptional regulation of ASK1 and Wip1. J Biol Chem. 2006;281:31309–16.
Article CAS PubMed Google Scholar
Jiang C-F, Wen L-Z, Yin C, Xu W-P, Shi B, Zhang X et al. Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4α on hepatocellular carcinoma. Oncotarget. 2016;7.
Maruyama T, Araki T, Kawarazaki Y, Naguro I, Heynen S, Aza-Blanc P, et al. Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Sci Signal. 2014;7:ra8–8.
Article PubMed Google Scholar
Nishida T, Hattori K, Watanabe K. The regulatory and signaling mechanisms of the ASK family. Adv Biol Regul. 2017;66:2–22.
Article CAS PubMed Google Scholar
Tarapore RS, Yang Y, Katz JP. Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival. Neoplasia. 2013;15:472–IN3.
Article CAS PubMed PubMed Central Google Scholar
Li W, **ong Y, Shang C, Twu KY, Hang CT, Yang J, et al. Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development. PNAS. 2013;110:1738–43.
Article CAS PubMed PubMed Central Google Scholar
Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, et al. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol. 2005;6:587–92.
Article CAS PubMed Google Scholar
Into T, Shibata K-i. Apoptosis signal-regulating kinase 1‐mediated sustained p38 mitogen‐activated protein kinase activation regulates mycoplasmal lipoprotein‐and staphylococcal peptidoglycan‐triggered toll‐like receptor 2 signalling pathways. Cell Microbiol. 2005;7:1305–17.
Article CAS PubMed Google Scholar
Yuk J-M, Shin D-M, Yang C-S, Kim KH, An S-J, Rho J, et al. Role of apoptosis-regulating signal kinase 1 in innate immune responses by Mycobacterium bovis bacillus Calmette-Guérin. Immunol Cell Biol. 2009;87:100–7.
Article CAS PubMed Google Scholar
Yang C-S, Shin D-M, Lee H-M, Son JW, Lee SJ, Akira S, et al. ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cell Microbiol. 2008;10:741–54.
Article CAS PubMed Google Scholar
Okazaki T. ASK family in infection and inflammatory disease. Adv Biol Regul. 2017;66:37–45.
Article CAS PubMed Google Scholar
Guo X, Harada C, Namekata K, Matsuzawa A, Camps M, Ji H, et al. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1‐p38 pathway. EMBO Mol Med. 2010;2:504–15.
Article CAS PubMed PubMed Central Google Scholar
Cheon SY, Kim EJ, Kim JM, Kam EH, Ko BW, Koo B-N. Regulation of microglia and macrophage polarization via apoptosis signal-regulating kinase 1 silencing after ischemic/hypoxic injury. Front Mol Neurosci. 2017;10:261.
Article PubMed PubMed Central Google Scholar
Song J, Lee JE. ASK1 modulates the expression of microRNA Let7A in microglia under high glucose in vitro condition. Front Cell Neurosci. 2015;9.
Lin H-Y, Tsai C-H, Lin C, Yeh W-L, Tsai C-F, Chang P-C, et al. Cobalt protoporphyrin upregulates cyclooxygenase-2 expression through a heme oxygenase-independent mechanism. Mol Neurobiol. 2016;53:4497–508.
Article CAS PubMed Google Scholar
Shi X, Seldin David C, Garry Daniel J. Foxk1 recruits the Sds3 complex and represses gene expression in myogenic progenitors. Biochem J. 2012;446:349–57.
Article CAS PubMed Google Scholar

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Acknowledgements

This project was supported by funds from the National Key Research and Development Program of China (No. 2022YFF0710200 and 2022YFC2406300), and the National Natural Science Foundation of China (No. 32341005, No. 32371205 and No. 32171438). This project was also supported by funds from the State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University. We thank the mass spectrometry Core at the National Center for Protein Science at Peking University, for assistance with the proteomic study.

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Jian Shen and Wenjia Lai contributed equally to this work.

Authors and Affiliations

Department of General Surgery, Bei**g Chao-Yang Hospital, Capital Medical University, Bei**g, 100020, China
Jian Shen
State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Bei**g, 100871, China
Zeyang Li, Wenyuan Zhu, Xue Bai, Zihao Yang, Qingsong Wang & Jianguo Ji
Division of Nanotechnology Development, National Center for Nanoscience and Technology, Bei**g, 100190, China
Wenjia Lai

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Jian Shen
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Zeyang Li
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Xue Bai
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Zihao Yang
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Qingsong Wang
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Jianguo Ji
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Jian Shen, Zeyang Li and Jianguo Ji conceived and designed the study; Wenjia Lai, Zeyang Li and Zihao Yang analyzed and interpreted the data; Zeyang Li and Xue Bai carried out the experiment; Wenjia Lai and Jian Shen wrote the main manuscript; Qingsong Wang and Jianguo Ji reviewed the article and provided comments. All the authors reviewed and approved the final manuscript.

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Correspondence to Qingsong Wang or Jianguo Ji.

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Communicated by Jianxiong Jiang.

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Shen, J., Lai, W., Li, Z. et al. SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway. Inflamm. Res. (2024). https://doi.org/10.1007/s00011-024-01913-5

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Received: 07 March 2024
Revised: 20 June 2024
Accepted: 03 July 2024
Published: 15 July 2024
DOI: https://doi.org/10.1007/s00011-024-01913-5

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SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway

Abstract

Background

Methods

Results

Conclusions

Introduction

SDS3 regulates the activation of p38 MAPK

SDS3 regulates the expression of ASK1

ASK1 regulates microglial inflammatory processes through the p38 MAPK signaling pathway

ASK1 knockout affects the regulation of SDS3 and the inflammatory response

Discussion

Conclusion

Data availability

References

Acknowledgements

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Authors and Affiliations

Contributions

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Competing interests

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