The Skin–Liver Axis Modulates the Psoriasiform Phenotype and Involves Leucine-Rich α-2 Glycoprotein

Nakajima, Hideki; Nakajima, Kimiko; Takaishi, Mikiro; Ohko, Kentaro; Serada, Satoshi; Fujimoto, Minoru; Naka, Tetsuji; Sano, Shigetoshi

doi:10.4049/jimmunol.2000502

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…Among those, autoimmune diseases are particularly disabling conditions representing a major hurdle both in terms of diagnosis and treatment. In particular, serum LRG1 has been identified as a useful biomarker for monitoring disease activity in patients with adult-onset Still's disease [ 138 ], psoriasis [ 65 , 139 , 140 ] lupus nephritis [ 17 ], rheumatoid arthritis [ 141 – 144 ] and vasculitis [ 145 – 149 ]. However, the role of LRG1 in these conditions remains largely unclear.…”

Section: Reviewmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

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Section: Reviewmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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“…Studies have shown that persistently high levels of LRG1 can maintain an inflammatory response and promote disease progression through a wide range of biological functions [22]. At present, it has been reported that LRG1 might be a useful biomarker to detect the occurrence of psoriasis in adults [23][24][25]. The development of new biomarkers has an urgent clinical need for early diagnosis and management of certain inflammatory diseases, and LRG1 is regulated by various pro-inflammatory cytokines, making it a highly promising candidate drug target for development [26].…”

Section: Discussionmentioning

confidence: 99%

Keratinocyte-to-macrophage communication exacerbate psoriasiform dermatitis via LRG1-enriched extracellular vesicles

Jiang,

Zhang,

Qiu

et al. 2024

Theranostics

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Rationale: Macrophage-associated inflammation and keratinocytes excessive proliferation and inflammatory cytokines secretion induced by stimulation play an important role in the progression of psoriasiform dermatitis. However, how these two types of cells communicate remains obscure. Methods:We induced a mouse model with experimental psoriasiform dermatitis by Imiquimod (IMQ). To investigate whether damaged keratinocytes promote macrophage polarization and accelerate skin lesions by releasing extracellular vesicle (EV), purified EV were isolated from the primary epidermis of 5-day IMQ-induced psoriasiform dermatitis model mice, and then fluorescence-labeled the EV with PKH67. The EV was injected into the skin of mice treated with IMQ or vehicle 2 days in situ. In addition, we established a co-culture system of the human monocytic cell line (THP-1) and HaCaT, and THP-1/HaCaT conditioned media culture model in vitro respectively. Subsequently, we evaluated the effect of Leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EV on macrophage activation. Results:We demonstrated macrophages can significantly promote keratinocyte inflammation and macrophage polarization may be mediated by intercellular communication with keratinocytes. Interestingly, IMQ-induced 5-day, keratinocyte-derived EV recruited macrophage and enhanced the progression of skin lesions. Similar to results in vivo, EV released from M5-treated HaCaT significantly promotes Interleukin 1β (IL-1β) and Tumor necrosis factor α (TNF-α) expression of THP-1 cells. Importantly, we found that LRG1-enriched EV regulates macrophages via TGF beta Receptor 1 (TGFβR1) dependent process. Conclusion:Our findings indicated a novel mechanism for promoting psoriasiform dermatitis, which could be a potential therapeutic target.

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“…In addition to adiponectin, other factors have been suggested to be involved in the liver–skin axis. Leucine-rich α-2 glycoprotein (LRG) modulates the liver–skin axis and is involved in the pathogenesis of psoriasiform inflammation ( 44 ). LRG deficiency resulted in mild psoriatic skin changes associated with decreased inflammatory cytokine expression in a murine model of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Co-occurrence of non-alcoholic steatohepatitis exacerbates psoriasis associated with decreased adiponectin expression in a murine model

Takezaki,

Morizane,

Ikeda

et al. 2023

Front. Immunol.

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IntroductionClinical studies have suggested a bidirectional association between non-alcoholic steatohepatitis (NASH) and psoriasis, affecting each other’s development and severity. Here, we explored bidirectional causal linkages between NASH and psoriasis using a murine model.MethodsNASH was induced in mice by streptozotocin injection at 2 days of age and by high-fat diet feeding (STAM™ model). Psoriasis was induced by topical application of imiquimod (IMQ) on the ear. The severities of liver damage and psoriatic skin changes were determined using histological analysis. Gene expression in the skin tissues was evaluated using quantitative PCR analysis. Serum cytokine levels were determined using enzyme-linked immunosorbent assay. To examine the innate immune responses of normal human epidermal keratinocytes (NHEKs), the cells were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, and AdipoRon, an adiponectin receptor agonist.Results and DiscussionThere were no differences in the degree of liver tissue damage (fat deposition, inflammation, and fibrosis) between NASH mice with and those without psoriasis. Conversely, the co-occurrence of NASH significantly augmented psoriatic skin changes, represented by epidermal hyperplasia, in psoriatic mice. Pro-inflammatory cytokines were expressed in the inflamed skin of psoriatic mice, and the expression of genes, especially Il23a, Il1b, Il36g, and Mip2, was significantly upregulated by the co-occurrence of NASH. The expression of keratinocyte activation marker genes Defb4b and Krt16 was also upregulated by the co-occurrence of NASH. The serum TNF-α and IL-17 levels were increased by the co-occurrence of NASH and psoriasis. The serum adiponectin levels decreased in NASH mice compared with that in non-NASH mice. In NHEK culture, TNF-α and IL-17A synergistically upregulated CXCL1, CXCL8, and IL1B expression. The upregulated pro-inflammatory gene expression was suppressed by AdipoRon treatment, reflecting the anti-inflammatory capacity of adiponectin.ConclusionThe co-occurrence of NASH exacerbated psoriatic skin changes associated with increased serum inflammatory cytokine levels and decreased serum adiponectin levels. Combined with in vitro findings, increased inflammatory cytokine levels and decreased adiponectin levels likely promote innate immune responses in epidermal keratinocytes in psoriatic skin lesions. Overall, therapeutic intervention for co-occurring NASH is essential to achieve a favorable prognosis of psoriasis in clinical practice.

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The Skin–Liver Axis Modulates the Psoriasiform Phenotype and Involves Leucine-Rich α-2 Glycoprotein

Cited by 8 publications

References 44 publications

LRG1: an emerging player in disease pathogenesis

LRG1: an emerging player in disease pathogenesis

Keratinocyte-to-macrophage communication exacerbate psoriasiform dermatitis via LRG1-enriched extracellular vesicles

Co-occurrence of non-alcoholic steatohepatitis exacerbates psoriasis associated with decreased adiponectin expression in a murine model

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