Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

Chong, Heng Thay; Yang, Gink N.; Sidhu, Shireen; Ibbetson, Jan; Kopecki, Zlatko; Cowin, Allison J.

doi:10.1111/bjd.14842

Cited by 15 publications

(29 citation statements)

References 28 publications

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“…The IMQ mouse model of psoriasiform dermatitis is one of the most utilized animal models in psoriasis research and has phenotypical features of human psoriasis [ 19 ]. Daily application of IMQ cream over a period of 6 days results in increased immune response resulting in erythema, swelling and scales [ 20 ]. While this model is widely used, to the best of our knowledge, this model has only been used to study acute and chronic forms of psoriasis and no previous studies have utilized this model to examine Trm cell levels in acute, chronic and resolved psoriasis-like dermatitis.…”

Section: Resultsmentioning

confidence: 99%

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

Fenix

Wijesundara

Cowin

et al. 2020

IJMS

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Psoriasis is a common chronic inflammatory skin condition manifested by T cell responses and characterized by preferential recurrence at previously inflamed sites upon withdrawal of treatment. The site-specific disease memory in psoriasis has been linked to CD8+CD103+ tissue-resident memory T cells (Trm) in the epidermis which were previously thought to only provide “frontline” protection against pathogens and immunosurveillance during cancer development. In this study, we correlated the presence of a subset of the Trm cells which are also CD49a+ with disease severity in human psoriatic lesions with acute and chronic disease. Using an imiquimod (IMQ)-induced murine model of psoriasiform dermatitis, we also investigated the level of CD49a+ Trm cells in acute, chronic and resolved psoriatic lesions. Investigation of clinical human samples showed that patient disease severity highly correlated with the numbers of epidermal CD49a+ Trm cells. Additionally, this subset of Trm cells was shown to persist in resolved lesions of murine psoriasiform dermatitis once clinical disease features had subsided. Importantly, these CD49a+ Trm cells showed significantly higher levels of granzyme B (GzmB) production compared to acute disease, suggesting a potential role of CD49a+ Trm cells for psoriatic re-occurrence in resolved patients. Better understanding of epidermal CD49a+ Trm cell activity is necessary for development of advanced treatment strategies for psoriasis to permit long-term, continuous disease control.

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Section: Resultsmentioning

confidence: 99%

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

Fenix

Wijesundara

Cowin

et al. 2020

IJMS

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“…LRRFIP-1’s role in TLR signaling and innate inflammatory responses has also been linked to its interactions with a negative regulator of wound healing, Flii, where LRRFIP-1 competes with Flii for the binding to the MyD88 and hence counteracts the effects of Flii on inflammation signaling pathways [ 11 ]. Our studies have investigated the role of Flii as a negative regulator of healing in both acute and chronic wound pathologies and most recently in the inflammatory skin condition psoriasis [ 2 , 16 , 17 , 18 ]. We have also shown that application of Flii-neutralizing antibodies to wounds in vivo neutralizes extracellular Flii, resulting in improved wound re-epithelialization, decreased tissue inflammation, increased cellular proliferation and migration, and significantly decreased early scar formation in both small and large animal models of wound repair [ 2 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant Leucine-Rich Repeat Flightless-Interacting Protein-1 Improves Healing of Acute Wounds through Its Effects on Proliferation Inflammation and Collagen Deposition

Kopecki

Stevens

Yang

et al. 2018

IJMS

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Wound healing is an increasing clinical problem involving substantial morbidity, mortality, and rising health care costs. Leucine-rich repeat flightless-interacting protein-1 (LRRFIP-1) regulates toll-like receptor (TLR)-mediated inflammation, suggesting a potential role in the healing of wounds. We sought to determine the role of LRRFIP-1 in wound repair and whether the exogenous addition of recombinant LRRFIP-1 (rLRRFIP-1) affected healing responses. Using a model of full-thickness incisional acute wounds in BALB/c mice, we investigated the effect of wounding on LRRFIP-1 expression. The effect of rLRRFIP-1 on cellular proliferation, inflammation, and collagen deposition was also investigated. LRRFIP-1 was upregulated in response to wounding, was found to directly associate with flightless I (Flii), and significantly increased cellular proliferation both in vitro and in vivo. rLRRFIP-1 reduced Flii expression in wounds in vivo and resulted in significantly improved healing with a concurrent dampening of TLR4-mediated inflammation and improved collagen deposition. Additionally, decreased levels of TGF-β1 and increased levels of TGF-β3 were observed in rLRRFIP-1-treated wounds suggesting a possible antiscarring effect of rLRRFIP-1. Further studies are required to elucidate if the mechanisms behind LRRFIP-1 action in wound repair are independent of Flii. However, these results identify rLRRFIP-1 as a possible treatment modality for improved healing of acute wounds.

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“…Flii also directly affects the immune response, altering macrophage activation and cytokine production in vitro and increasing Flii expression in diabetic wounds is associated with increased NF-κB production and a prolonged inflammatory phase is observed in the healing of incisional wounds of mice [79][80][81]. The application of a Flii neutralising antibody in an animal model of the inflammatory skin condition, psoriasis, reduces pro-inflammatory cytokine expression and immune cell infiltration [82]. By treating mouse burn wounds with this antibody and reducing the expression of Flii, it was possible to decrease TGF-β1 levels and cause faster wound healing with less scar formation in mice [83] (Figure 4).…”

Section: Interruption Of Immune Signalling Pathwaysmentioning

confidence: 99%

The Role of the Inflammatory Response in Burn Injury

Strudwick¹,

Cowin²

2018

Hot Topics in Burn Injuries

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Burns are characterised by significant local swelling and redness around the site of injury, indicative of acute inflammation. Whilst the inflammatory response is fundamental to the healing process, triggering a cascade of cytokines and growth factors to protect against the risk of infection, it is clear that prolonged inflammation can be detrimental and lead to scarring and fibrosis. Severe burns may display chronic, persistent inflammation long after the initial burn injury and may even result in multiple organ failure (MOF) due to systemic inflammatory response syndrome (SIRS). Excessive inflammation in the early stages of healing has been identified as a causative factor in the formation of scars which can be disfiguring, functionally restrictive and may require revisionary surgeries. Therefore, it is imperative that inflammation is effectively managed following burn injuries in order to optimise the benefits it provides whilst actively preventing the complications of inflammation including SIRS, multiple organ failure (MOF) and the development of scarring and fibrosis. Reviewing the current knowledge about the role of the inflammatory response in burns and the treatments available for the management of inflammation during wound healing, highlights the importance of continued research into understanding and developing new approaches to regulate inflammatory responses post-burn injuries.

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Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

Abstract: Flii is a novel target involved in psoriasiform dermatitis and reducing cutaneous Flii could potentially be a new approach for treating patients with psoriasis.

Cited by 15 publications

References 28 publications

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

Recombinant Leucine-Rich Repeat Flightless-Interacting Protein-1 Improves Healing of Acute Wounds through Its Effects on Proliferation Inflammation and Collagen Deposition

The Role of the Inflammatory Response in Burn Injury

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