Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Hall, Cathy W.; Sanderson, Leslie E.; Lawrence, Lisa M.; Pool, Bregina; Kroef, Maarten van der; Ashimbayeva, Elina; Britto, Denver D.; Harper, Jacquie L.; Lieschke, Graham J.; Astin, Jonathan W.; Crosier, Kathryn E.; Dalbeth, Nicola; Crosier, Philip S.

doi:10.1172/jci94584

Cited by 51 publications

(52 citation statements)

References 75 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that all graft types could induce both immune cell recruitment and vascularisation, we wondered whether leukocytes had a role in the angiogenic response. We conducted clodronate-mediated macrophage ablation to specifically induce macrophage death in grafted larvae (Hall et al, 2018; Astin et al, 2017; Carrillo et al, 2016; Lai et al, 2017). The efficacy of macrophage reduction was assessed by measuring the difference in the number of graft-associated macrophages in larvae injected with clodronate-containing liposomes and larvae injected with PBS-containing liposomes.…”

Section: Resultsmentioning

confidence: 99%

Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model

Britto

Wyroba

Chen

et al. 2018

Disease Models &Amp; Mechanisms

Self Cite

View full text Add to dashboard Cite

Tumour angiogenesis has long been a focus of anti-cancer therapy; however, anti-angiogenic cancer treatment strategies have had limited clinical success. Tumour-associated myeloid cells are believed to play a role in the resistance of cancer towards anti-angiogenesis therapy, but the mechanisms by which they do this are unclear. An embryonic zebrafish xenograft model has been developed to investigate the mechanisms of tumour angiogenesis and as an assay to screen anti-angiogenic compounds. In this study, we used cell ablation techniques to remove either macrophages or neutrophils and assessed their contribution towards zebrafish xenograft angiogenesis by quantitating levels of graft vascularisation. The ablation of macrophages, but not neutrophils, caused a strong reduction in tumour xenograft vascularisation and time-lapse imaging demonstrated that tumour xenograft macrophages directly associated with the migrating tip of developing tumour blood vessels. Finally, we found that, although macrophages are required for vascularisation in xenografts that either secrete VEGFA or overexpress zebrafish vegfaa, they are not required for the vascularisation of grafts with low levels of VEGFA, suggesting that zebrafish macrophages can enhance Vegfa-driven tumour angiogenesis. The importance of macrophages to this angiogenic response suggests that this model could be used to further investigate the interplay between myeloid cells and tumour vascularisation.

show abstract

Section: Resultsmentioning

confidence: 99%

Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model

Britto

Wyroba

Chen

et al. 2018

Disease Models &Amp; Mechanisms

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, Simiao decoction could reduce STAT3, a component of the IL-6-activated acute phase response factor ( Fielding et al, 2008 ) that was activated in the pathological status, to a nearly normal level. STAT3 inhibition could result in the suppressed TNF-α and IL-1β production in response to MSU crystals ( Hall et al, 2018 ). Besides, the transcription factor AP-1 also reduced production of TNF-α and IL-1β ( Hsiang et al, 2005 ; Bashir et al, 2009 ) The expression of c-FOS, one component of AP-1, was decreased by Simiao decoction.…”

Section: Discussionmentioning

confidence: 99%

Simiao Decoction Alleviates Gouty Arthritis by Modulating Proinflammatory Cytokines and the Gut Ecosystem

et al. 2020

View full text Add to dashboard Cite

Simiao decoction, a classical traditional Chinese medicine (TCM) formula, has been widely used for thousands of years due to its safety and efficiency in treating gouty arthritis. Utilizing serum proinflammatory cytokines and gut ecosystems, this study elucidated the mechanisms of alleviating gouty arthritis by Simiao decoction. Simiao decoction (4.0, 8.0, and 16.0 g/kg) was orally administered to gouty arthritis mice and febuxostat was given as a positive control. The spleen, kidney, and liver indexes indicated that Simiao decoction was safe for the treatment of gouty arthritis in C57BL/6 mice. Besides, our study demonstrated that Simiao decoction was effective for reducing the level of serum uric acid and decreasing MPO, XOD, and ADA activity, as well as alleviating gouty-related symptoms, such as foot swelling and pain. Moreover, Simiao decoction could also reduce some specific serum proinflammatory cytokines including IL-1b, IL-9, IFN-g, MIP-1a and MIP-1b. We then surveyed the effects of Simiao decoction on the gut ecosystems in a systematic manner by combining network pharmacology, ELISA, western blot, and illumina sequencing. In the murine of model of gouty arthritis, Simiao decoction could suppress NLRP3 inflammasomes expression, reduce gut apoptosis through modulating TNF-a, Caspase 8, and AIFM1 protein expressions, affect lipid metabolism by regulating APOB, LPL, PPARa protein expressions and restore gut microbiota via reducing potential pathogens. Overall, these findings suggested that Simiao decoction was an effective therapeutic drug for gouty arthritis and the gut ecosystem might act as a potential antiinflammatory target of Simiao decoction.

show abstract

“…Similar to that observed during infection, the host response to such "sterile" insults is dominated by the recruitment of phagocytic cells, in particular neutrophils and macrophages. The zebrafish offers several established models of sterile inflammation, from acute injury and chemical insults to crystal injections ( Figure 1B) (105)(106)(107)(108). The following section describes studies that have utilized zebrafish models of sterile inflammation and uncovered mechanistic insights into how neutrophil numbers are controlled during sterile inflammation and how macrophages help orchestrate neutrophil migration.…”

Section: Phagocyte Responses During Sterile Inflammationmentioning

confidence: 99%

“…The MSU crystal deposition causes an acute inflammatory reaction, termed a gout flare, which is extremely painful and usually self-resolves within 1-2 weeks (126). Our group has recently developed a larval zebrafish model of gout to provide new insights into how phagocytes become activated in response to crystal-induced sterile inflammation (108). In this novel zebrafish model, MSU crystals, the causative agent in the development of gouty flares, were locally injected into the hindbrain ventricle of zebrafish larvae.…”

Section: Chemical and Crystal-induced Inflammationmentioning

confidence: 99%

“…The acute inflammatory reaction in the human condition is often connected to increased consumption of alcohol and purine-rich foods, which results in the substantial release of fatty acids (FAs) into the circulation (127). By live imaging metabolic processes [such as mitochondrial ROS (mROS) production; (128)] within macrophages during MSU-driven crystal inflammation, we were able to demonstrate that β-oxidation of FAs fueled macrophage activation through elevated mROS production (108). Moreover, this immunometabolic mechanism was conserved in human macrophages.…”

Section: Chemical and Crystal-induced Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

The Diverse Roles of Phagocytes During Bacterial and Fungal Infections and Sterile Inflammation: Lessons From Zebrafish

Linnerz

Hall

2020

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

The immediate and natural reaction to both infectious challenges and sterile insults (wounds, tissue trauma or crystal deposition) is an acute inflammatory response. This inflammatory response is mediated by activation of the innate immune system largely comprising professional phagocytes (neutrophils and macrophages). Zebrafish (danio rerio) larvae possess many advantages as a model organism, including their genetic tractability and highly conserved innate immune system. Exploiting these attributes and the live imaging potential of optically transparent zebrafish larvae has greatly contributed to our understanding of how neutrophils and macrophages orchestrate the initiation and resolution phases of inflammatory responses. Numerous bacterial and fungal infection models have been successfully established using zebrafish as an animal model and studies investigating neutrophil and macrophage behavior to sterile insults have also provided unique insights. In this review we highlight how examining the larval zebrafish response to specific bacterial and fungal pathogens has uncovered cellular and molecular mechanisms behind a variety of phagocyte responses, from those that protect the host to those that are detrimental. We also describe how modeling sterile inflammation in larval zebrafish has provided an opportunity to dissect signaling pathways that control the recruitment, and fate, of phagocytes at inflammatory sites. Finally, we briefly discuss some current limitations, and opportunities to improve, the zebrafish model system for studying phagocyte biology.

show abstract

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Cited by 51 publications

References 75 publications

Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model

Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model

Simiao Decoction Alleviates Gouty Arthritis by Modulating Proinflammatory Cytokines and the Gut Ecosystem

The Diverse Roles of Phagocytes During Bacterial and Fungal Infections and Sterile Inflammation: Lessons From Zebrafish

Contact Info

Product

Resources

About