Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration

Yang, Chen; Cao, Peng; Gao, Yang; Wu, Ming; Lin, Yun; Tian, Ye; Yuan, Wen

doi:10.1038/srep22182

Cited by 60 publications

(82 citation statements)

References 44 publications

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“…Nonetheless, a detailed analysis of immune cell recruitment to herniated IVD is still lacking. Since an antigen-specific immune response has been considered in case of hernia regression [41], it would be relevant in the future to follow that immune cell recruitment to the injury site by analyzing the cellular content in the IVD, hernia, BL, LN and SP at different time points, namely in the acute inflammatory response. Our results also evidence the importance of looking to both local and systemic inflammatory and immune cell responses in vivo to better understand the dynamic nature of the immune response to IVD herniation.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

Cunha

Teixeira

Ribeiro-Machado

et al. 2020

IJMS

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Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO-versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, known as pro-inflammatory (PRO), and soluble diclofenac, a non-steroidal anti-inflammatory drug (ANTI), were intradiscally administered in a rat IVD injury model, 24 h after lesion. Two weeks after administration, a reduction of disc height accompanied by hernia formation was observed. In the PRO-inflammatory treated group, IL-1β, IL-6 and COX-2 IVD gene expression were upregulated, and loss of nucleus pulposus (NP) structure and composition was observed. Systemically, lower T-cell frequency was observed in the lymph nodes (LN) and spleen (SP) of the PRO group, together with an increase in CD4+ T cells subset in the blood (BL) and LN. In contrast, the ANTI-group had higher proteoglycans/collagen ratio and collagen type 2 content in the NP, while an increase in the frequency of myeloid cells, M1 macrophages and activated macrophages (MHCII+) was observed at the systemic level. Overall, this study illustrates the dynamics of local and systemic inflammatory and immune cell responses associated with intradiscal therapies, which will contribute to designing more successful immunomodulatory treatments for IVD degeneration.Several in vivo models of IVD degeneration are described in the literature, with murine tail models of mechanical injury by needle puncture commonly used [4,5]. Depending on the needle size, the puncture may induce annulus fibrosus (AF) disruption while causing depressurization of the nucleus pulposus (NP) [6,7]. Needle calibers, varying between 16 to 22 G, often lead to significant pressure failure, decreased cell viability, increased expression of pro-inflammatory/degenerative factors and alterations in extracellular matrix (ECM) composition in IVDs from both large (e.g., bovine [8]) and small animals (e.g., rabbit [9] and rat [10]), resembling human IVD degeneration. Our group has previously established and validated an IVD herniation/degeneration model of rat caudal needle puncture, using a 21 G needle [10,11], in which IVD herniation and infiltration of macrophages were observed [10]. This model is relatively simple to manipulate and presents cost-effectiveness [12]. Moreover, it allows the study of local and systemic immune response, crucial in human IVD degeneration and difficult to analyze in vitro or ex vivo [13]. Only a few studies, mainly in bone, address the dialogue/interplay between local/systemic immune responses and how this can be linked with tissue remodeling [14,15]. Despite this, it is important to consider the limitations of small animal models of IVD degeneration when compared to humans, such as differences in spine biomechanics, IVD size and cellular composition, which may be critical for clinical trans...

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Section: Discussionmentioning

confidence: 99%

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

Cunha

Teixeira

Ribeiro-Machado

et al. 2020

IJMS

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“…Activation of NF-kB and mitogen-activated protein kinases (MAPKs) has been implicated in the M1 phenotypic switch (21,22); therefore, we investigated the involvement of these signaling pathways in LPS-stimulated M1 polarization conditions. NF-kB activity, as assessed by p65 and IKKa/b phosphorylation, was increased in BMMs from mS6KO mice compared with those from WT mice (Fig.…”

Section: Activation Of the Nf-kb-il-6-stat3 Axis Is Involved In M1 Pomentioning

confidence: 99%

Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet–Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype

Lee

Cha

et al. 2017

Diabetes

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Obesity-related insulin resistance is closely associated with macrophage accumulation and subsequent cytokine release in local tissues. Sirtuin 6 (Sirt6) is known to exert an anti-inflammatory function, but its role in macrophages in the context of obesity has not been investigated. We generated myeloid-specific Sirt6 knockout (mS6KO) mice and investigated the metabolic characteristics after high-fat diet (HFD) feeding for 16 weeks. Compared with their wild-type littermates, HFD-fed mS6KO mice exhibited greater increases in body weight, fasting blood glucose and insulin levels, hepatic steatosis, glucose intolerance, and insulin resistance. Gene expression, histology, and flow cytometric analyses demonstrated that liver and adipose tissue inflammation were elevated in HFD-fed mS6KO mice relative to wild type, with a greater accumulation of F4/80CD11bCD11c adipose tissue macrophages. Myeloid Sirt6 deletion facilitated proinflammatory M1 polarization of bone marrow macrophages and augmented the migration potential of macrophages toward adipose-derived chemoattractants. Mechanistically, Sirt6 deletion in macrophages promoted the activation of nuclear factor-κB (NF-κB) and endogenous production of interleukin-6, which led to STAT3 activation and the positive feedback circuits for NF-κB stimulation; this cross talk expedited an M1 polarization. We conclude that Sirt6 in macrophages is required for the prevention of obesity-associated tissue inflammation and insulin resistance.

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“…MAPK pathway was also identified as a potential therapeutic target for control of anti-catabolic and anti-inflammatory situations in IVD. Suppression of MAPK pathway could also regulate integrin expression, matrix production, osmosis, and cell survival of IVD cells (Yang et al, 2016 ). Inhibition of p38 MAPK successfully suppressed secretion of pro-inflammatory cytokines while restoring proteoglycan synthesis in AF cells.…”

Section: Biological Treatments Of Afmentioning

confidence: 99%

Strategies for Annulus Fibrosus Regeneration: From Biological Therapies to Tissue Engineering

Chu

Shi

Wang

et al. 2018

Front. Bioeng. Biotechnol.

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Intervertebral disc (IVD) is an avascular tissue which contributes to the weight bearing, motion, and flexibility of spine. However, IVD is susceptible to damage and even failure due to injury, pathology, and aging. Annulus fibrosus (AF), the structural and functional integrity of which is critically essential to confine nucleus pulpous (NP) and maintain physiological intradiscal pressure under mechanical loading, plays a critical role in the biomechanical properties of IVD. AF degeneration commonly results in substantial deterioration of IVD. During this process, the biomechanical properties of AF and the balance between anabolism and catabolism in IVD are progressively disrupted, leading to chronic back pain, and even disability of individuals. Therefore, repairing and regenerating AF are effective treatments to degeneration-associated pains. However, they remain highly challenging due to the complexity of natural AF tissue in the aspects of cell phenotype, biochemical composition, microstructure, and mechanical properties. Tissue engineering (TE), by combining biological science and materials engineering, shed lights on AF regeneration. In this article, we review recent advances in the pro-anabolic approaches in the form of cell delivery, bioactive factors delivery, gene therapy, and TE strategies for achieving AF regeneration.

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Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration

Cited by 60 publications

References 44 publications

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet–Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype

Strategies for Annulus Fibrosus Regeneration: From Biological Therapies to Tissue Engineering

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