Skin inflammation leads immunoglobulin G aggregation and deposition in multiple organs

Yamanaka, Keiichi; Okada, K.; Nakanishi, Takehisa; Mizutani, Kazuki; Matsushima, Yoshiaki; Kondo, Makoto; Habe, Koji; Mizutani, Hitoshi; Seo, Naohiro

doi:10.1016/j.jdermsci.2017.05.013

Cited by 8 publications

(11 citation statements)

References 5 publications

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“…A previous study showed chronic skin inflammation induces the aberrant remodeling of vascular tissues, potentially resulting in atherosclerosis [11]. Systemic amyloidosis with functional deterioration has also been seen in inflammatory skin conditions [12]. The erupted skin of KCASP1Tg mice produces significantly higher amounts of IL-1α and β compared to normal skin, while the supernatant from skin lesions leads to a severe reduction in lipid particles in an adipocyte culture system [10].…”

Section: Discussionmentioning

confidence: 99%

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Mizutani

Shirakami

Ichishi

et al. 2020

IJMS

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Adipose tissue (AT) is the largest endocrine organ, producing bioactive products called adipocytokines, which regulate several metabolic pathways, especially in inflammatory conditions. On the other hand, there is evidence that chronic inflammatory skin disease is closely associated with vascular sclerotic changes, cardiomegaly, and severe systemic amyloidosis in multiple organs. In psoriasis, a common chronic intractable inflammatory skin disease, several studies have shown that adipokine levels are associated with disease severity. Chronic skin disease is also associated with metabolic syndrome, including abnormal tissue remodeling; however, the mechanism is still unclear. We addressed this problem using keratin 14-specific caspase-1 overexpressing transgenic (KCASP1Tg) mice with severe erosive dermatitis from 8 weeks of age, followed by re-epithelization. The whole body and gonadal white AT (GWAT) weights were decreased. Each adipocyte was large in number, small in size and irregularly shaped; abundant inflammatory cells, including activated CD4+ or CD8+ T cells and toll-like receptor 4/CD11b-positive activated monocytes, infiltrated into the GWAT. We assumed that inflammatory cytokine production in skin lesions was the key factor for this lymphocyte/monocyte activation and AT dysregulation. We tested our hypothesis that the AT in a mouse dermatitis model shows an impaired thermogenesis ability due to systemic inflammation. After exposure to 4 °C, the mRNA expression of the thermogenic gene uncoupling protein 1 in adipocytes was elevated; however, the body temperature of the KCASP1Tg mice decreased rapidly, revealing an impaired thermogenesis ability of the AT due to atrophy. Tumor necrosis factor (TNF)-α, IL-1β and interferon (INF)-γ levels were significantly increased in KCASP1Tg mouse ear skin lesions. To investigate the direct effects of these cytokines, BL/6 wild mice were administered intraperitoneal TNF-α, IL-1β and INF-γ injections, which resulted in small adipocytes with abundant stromal cell infiltration, suggesting those cytokines have a synergistic effect on adipocytes. The systemic dermatitis model mice showed atrophy of AT and increased stromal cells. These findings were reproducible by the intraperitoneal administration of inflammatory cytokines whose production was increased in inflamed skin lesions.

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Section: Discussionmentioning

confidence: 99%

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Mizutani

Shirakami

Ichishi

et al. 2020

IJMS

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“…The femur mRNA levels of genes involved in bone formation, including Alpl, Col1a1, and Bglap, were significantly downregulated; we speculated that serum osteocalcin would be decreased in KCASP1Tg mice. One characteristic complication in adult KCASP1Tg mice is renal dysfunction, which leads to the decreased excretion of osteocalcin, possibly explaining the similar level of serum osteocalcin observed in KCASP1Tg and wild-type mice [13,16]. On the other hand, the inflammatory cytokine, TNF-α, was significantly increased in the femur of KCASP1Tg mice.…”

Section: Discussionmentioning

confidence: 86%

Inflammatory Skin-Derived Cytokines Accelerate Osteoporosis in Mice with Persistent Skin Inflammation

Mizutani

Isono

Matsushima

et al. 2020

IJMS

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Secondary osteoporosis can also be caused by chronic inflammatory skin disease as well as rheumatoid arthritis or inflammatory bowel disease. However, the exact role of osteoporosis in inflammatory skin conditions has not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of osteoporosis in inflammatory skin conditions and the therapeutic impact of osteoporosis medication on inflammatory skin disease. We employed model mice of spontaneous skin inflammation, specifically overexpressing human caspase-1 in the epidermis. Bone density and the expression of various mRNAs in the femur were examined by micro CT and RT-PCR. The effects of minodronate and anti-RANKL antibody on bone structure, histology, and femur blood flow were studied. The mouse model of skin inflammation showed a marked decrease in bone density compared to wild-type littermates with abnormalities in both bone resorption and formation. Minodronate improved bone density by decreasing osteoclasts, but anti-RANKL antibody did not improve. In the dermatitis model, the blood flow in the bone marrow was decreased, and minodronate restored this parameter. A model of persistent dermatitis exhibited marked osteoporosis, but the impact of chronic dermatitis on osteoporosis has not been thoroughly investigated. We should explore the pathogenesis of osteoporosis in skin inflammatory diseases.

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“…The skin is one of the most critical immune organs, featuring skin-associated lymphoid tissues [16]; once irritated or activated, the skin produces and releases large amounts of inflammatory cytokines, which affect internal organs. We tested the sperm viability in two additional protocols.…”

Section: Discussionmentioning

confidence: 99%

“…Systemic amyloidosis with functional decline has also been observed in chronic inflammatory skin conditions. Histological examinations showed a dense amyloid and immunoglobulin G (IgG) deposition and loss of normal architecture in spleen, kidney, and liver [16]. In addition, KCASP1Tg mice gradually became emaciated as the dermatitis spreads.…”

Section: Introductionmentioning

confidence: 99%

Skin Inflammation and Testicular Function: Dermatitis Causes Male Infertility via Skin-Derived Cytokines

et al. 2020

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The medical comorbidities including skin diseases are associated with male infertility. The most common cause of male infertility is the inability of testes to produce sperm; however, the influence of persistent dermatitis on testicular function has not been elucidated so far. We investigated the relationship between skin inflammation and impaired sperm production using a spontaneous dermatitis mouse model. We examined the breeding records of dermatitis mice and their wild-type littermates. Sperm count, motility, and viability were analyzed by direct microscopic observation and flow cytometry. In addition, testis and epididymis were histologically examined. Finally, sperm viability was evaluated in another dermatitis mouse model and in wild-type mice in which inflammatory cytokines were intraperitoneally administered. Compared to wild-type littermate mice, the number of children born was lower in mice with dermatitis. The body weight and testis size were decreased age-dependently. In the skin disease group, the sperm count and movement ratio were clearly decreased, and reduced sperm viability was observed. Histological examination revealed the detachment of Sertoli cells and reduced spermatogenesis. The fibrosis of epididymal stroma was severe, and it might affect defective sperm maturation in the epididymis. In addition, this phenomena was reproduced by a hapten applied dermatitis mouse model and the intraperitoneal administration of inflammatory cytokines. Once the skin is inflamed, inflammatory cytokines are produced and released, which may affect testicular and sperm function. Additional studies are needed to determine the relationship between male infertility and severe dermatitis in human.

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Skin inflammation leads immunoglobulin G aggregation and deposition in multiple organs

Cited by 8 publications

References 5 publications

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Inflammatory Skin-Derived Cytokines Accelerate Osteoporosis in Mice with Persistent Skin Inflammation

Skin Inflammation and Testicular Function: Dermatitis Causes Male Infertility via Skin-Derived Cytokines

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