Inhibition of spinal p38 MAPK prevents articular neutrophil infiltration in experimental arthritis via sympathetic activation

Kanashiro, Alexandre; Franchin, Marcelo; Bassi, Gabriel Shimizu; Santana, Denis A.; Cunha, Thiago M.; Cunha, Fernando Q.; Ulloa, Luis; Rodrigues, Gerson Jhonatan

doi:10.1111/fcp.12338

Cited by 8 publications

(6 citation statements)

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“…Our findings are consistent with SH1293 slowing the disease trajectory in part via b 2 -AR signaling mediated via cAMP-PKA signal transduction. Existing data supports normal signaling via a-AR in IA, and our findings with SH1293 treatment are consistent with normal functioning of a-ARs in the talocrural joint tissues and inflammatory cells (47)(48)(49).…”

Section: Discussionsupporting

confidence: 87%

“…These findings support a transient anti-inflammatory effect of SH1293 that likely contributed to the reduced footpad widths in SH1293 rats. The a-AR antagonist activity of SH1293 may inhibit proinflammatory cytokine production (e.g., tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-17 and leukocyte extravasation (47)(48)(49). This effect may also result from the downregulation of b 2 -ARs in inflammatory cells and high sympathetic tone that is wellestablished in AA (23,30).…”

Section: Sh1293 Suppressed Inflammatory Cell Infiltrationmentioning

confidence: 99%

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Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

et al. 2021

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ObjectiveHypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis.MethodsComplete Freund’s adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization.ResultsOn D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint.Conclusion and SignificanceOur findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.

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Section: Discussionsupporting

confidence: 87%

Section: Sh1293 Suppressed Inflammatory Cell Infiltrationmentioning

confidence: 99%

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

et al. 2021

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“…We have used neutrophil recruitment as a biological signal of local/acute inflammation. We investigated neuromodulation of inflammation in experimental arthritis [25][26][27][28], using neutrophil migration as the main hallmark for local inflammation. Despite the key role of neutrophils in tissue damage, few studies investigated their role in the neural circuits, probably because of their short lifespan [29,30].…”

Section: Neuro-immune Interaction: Neutrophils In a Neuro-immune Contextmentioning

confidence: 99%

The role of neutrophils in neuro-immune modulation

Kanashiro

Hiroki

Fonseca

et al. 2020

Pharmacological Research

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110

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Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation *

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“…Rheumatoid arthritis is an autoimmune disease characterised by chronic inflammation, leading to bone and cartilage destruction within the joints. Upregulated P38 activity is a key contributor to this inflammatory response and a number of P38 inhibitors have been tested as potential treatments [6,54,101]. However, P38 inhibitors have failed to achieve significant disease attenuation in vivo, possibly because P38 has both pro-and anti-inflammatory effects [11,24].…”

Section: Joint Inflammation Arthritis and Bone Repairmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38-and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38-and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders. Keywords Apoptosis signal-regulating kinase 1. MAP3K5. Clinical trial. ROS. MAPK. p38. JNK Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), commonly known as apoptosis signal-regulating kinase 1 (ASK1), has emerged as a target for preventing p38 mitogen-activated protein kinase (MAPK14, 11, and 12/ P38α, β, and γ) and c-Jun N-terminal kinase (MAPK8, 9, and 10/JNK1, 2, and 3)-mediated cell death and disease. Both P38 and JNK are associated with reactive oxygen species (ROS)-induced disease 1 , and numerous studies have demonstrated that P38 and JNK inhibition ameliorates cell death [3-7]. However, complete inhibition of P38 or JNK in vivo is problematic, given that these ubiquitously expressed proteins are also critical for cell survival and homeostatic and/ or metabolic functions [8-11]. This is highlighted by the embryonic lethality of homozygous P38α and Jnk1/2 knockout mice [12, 13]. In addition, homozygous P38β knockout mice exhibit defective skeletal development [14] and homozygous Jnk1 knockout mice spontaneously develop intestinal tumours [15]. Negative outcomes have also been reported due to partial P38 or Jnk expression, with heterozygous P38α knockout mice developing progressive renal dysfunction [16] and heterozygous Jnk1 knockout mice exhibiting altered weight gain, hyperinsulinaemia, insulin resistance, inflammatory cytokine disruption, and reduced viability [17]. Serious side effects have also been observed when pharmacological inhibition of P38 or JNK is pursued in vivo [14, 18, 19]. For example, pamapimod, a P38 (α and β) inhibitor, did not significantly reduce joint swelling or improve mobility in individuals with rheumatoid arthritis in a phase II clinical trial. However, 35% of the participants receiving daily pamapimod (300 mg) experienced infection, 20% developed a skin rash, 15% became dizzy, and 13% had e...

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Inhibition of spinal p38 MAPK prevents articular neutrophil infiltration in experimental arthritis via sympathetic activation

Cited by 8 publications

References 34 publications

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

The role of neutrophils in neuro-immune modulation

ASK1 inhibition: a therapeutic strategy with multi-system benefits

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