Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.

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Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21155515 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5515

Author(s):

Kento Fujii ◽

Yasuko Yamamoto ◽

Yoko Mizutani ◽

Kuniaki Saito ◽

Mariko Seishima

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Skin Inflammation ◽

Kynurenine Pathway ◽

Immune Functions ◽

Wild Type ◽

Indoleamine 2,3 Dioxygenase ◽

Tnf Α ◽

In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

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Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms23010221 ◽

2021 ◽

Vol 23 (1) ◽

pp. 221

Author(s):

Vanesa Palau ◽

Josué Jarrín ◽

Sofia Villanueva ◽

David Benito ◽

Eva Márquez ◽

...

Keyword(s):

Endothelial Cells ◽

Mouse Model ◽

High Fat Diet ◽

Macrophage Infiltration ◽

Creatinine Ratio ◽

Wild Type ◽

High Fat ◽

Tnf Α ◽

Galectin 3 ◽

Factor Α

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

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PDE-9 Inhibition Combined with Hydroxyurea Is Beneficial in Vaso-Occlusive Crisis in Mouse Model of Sickle Cell Disease

Blood ◽

10.1182/blood.v124.21.2694.2694 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2694-2694 ◽

Cited By ~ 1

Author(s):

Reema Jasuja ◽

Sunita Patel Hett ◽

Joachim Fruebis ◽

Debra Pittman

Keyword(s):

Sickle Cell Disease ◽

Mouse Model ◽

Sickle Cell ◽

Neutrophil Adhesion ◽

Acute Inflammatory Response ◽

Wild Type ◽

Cell Disease ◽

Multicellular Aggregates ◽

Tnf Α ◽

Platelet Aggregates

Abstract Vaso-occlusion is the major cause of morbidity and mortality in sickle cell disease (SCD). It is a complex multistep process initiated by the adhesion of fragile red cells and leucocytes, primarily neutrophils, to the hypoxic and inflamed endothelium. Attachment of large and rigid neutrophils to the endothelium, particularly in the microcirculation induces vaso-occlusive crisis by activating neutrophils and forming multicellular aggregates with erythrocytes and platelets. Dysregulated nitric oxide (NO) homeostasis contributes to vascular dysfunction in SCD. Hydroxyurea is the standard of care and the only approved therapy for SCD. Hydroxyurea has been shown to exhibit NO donor properties and may act to increase g-globin expression via the second messenger cGMP. PF-04447943 (PDE9i) is a selective inhibitor of the cGMP specific phosphodiesterase-9A (PDE-9A) enzyme (IC50 12nM) being developed for the treatment of SCD. Here, we study the combined effects of this PDE-9A inhibitor and hydroxyurea in a mouse model of acute vaso-occlusion. The effect of PF-04447943 was assessed in the presence and absence of hydroxyurea in vivo using two models, TNF-α treated normal wild-type mice and the Townes model of SCD. C57BL/6J or Townes SCD mice were randomized to treatment with saline or PDE-9 inhibitor alone or in combination with hydroxurea. In wild-type mice, treatment was administered in a prophylactic setting prior to the TNF-α inflammatory challenge or in an acute setting post-TNF-α (0.5 ug/mouse). TNF-α induces a well described acute inflammatory response in the microcirculation associated with neutrophil adhesion to the endothelium and formation of multicellular aggregates. Alexa-488 labeled Ly-6G neutrophil antibody and Dylight-649 labeled CD42c platelet antibody was injected to quantify neutrophils adhered to endothelium and neutrophil-platelet aggregates. Mouse cremaster microvasculature was observed by intravital microscopy. TNF–α treatment of C57BL/6J mice increased the number of adherent neutrophils and neutrophil-platelet aggregates, and decreased the number of rolling neutrophils compared to vehicle treated mice. Treatment with PDE9i or hydroxyurea alone in TNF-α challenged mice had no significant effect on neutrophil adhesion. Co-administration of 100 mg/kg HU in combination with 10 mg/kg PDE9i prior to TNF-α challenge led to a 69% reduction in neutrophils adhered to the endothelium and 89% reduction in neutrophil-platelet aggregates compared to TNF–α treated mice alone. Neutrophil adhesion was also reduced 59% in mice receiving 50 mg/kg hydroxurea and 1 mg/kg PDE9i. There was a significant increase in the neutrophil rolling number and velocity after co-administration of PDE9i and HU in TNF-α challenged mice. However, mice receiving PDE9i and hydroxurea after theTNF-α challenge did not show significant changes in neutrophil adhesion or aggregates. Plasma levels of sP-Selectin, sE-Selectin, sVCAM-1 and sICAM-1 decreased when animals were given a prophylactic combination treatment with PDE9i and hydroxyurea. The Townes sickle cell disease mice exhibit an acute inflammatory response upon surgical exposition of the cremaster muscle and show increased number of adherent neutrophils and large neutrophil-platelet aggregates. Prophylactic treatment of these sickle mice with combination of PDE9i and hydroxyurea also showed a 63% reduction in neutrophil adhesion and a 75% reduction in cell aggregates, leading to reduced vaso-occlusion. In summary, inhibition of PDE9 in mouse models of SCD had beneficial effects in the prophylactic reduction of crisis. Co-administration of PDE9 inhibitor with hydroxyurea, led to a significant reduction in vaso-occlusion associated with sickle cell disease in two distinct animal models of SCD. All experiments were within guidelines and were reviewed and approved by the site institutional animal care and use committee. Disclosures No relevant conflicts of interest to declare.

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Improvement of granulomatous skin conditions with tofacitinib in three patients: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x211039477 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110394

Author(s):

Meghan L McPhie ◽

William C Swales ◽

Melinda J Gooderham

Keyword(s):

Skin Diseases ◽

Therapeutic Option ◽

Treatment Options ◽

Janus Kinase ◽

Jak Inhibitors ◽

Inflammatory Skin Diseases ◽

Efficacious Treatment ◽

Inflammatory Skin ◽

Granulomatous Disorder ◽

Skin Conditions

Granulomatous skin conditions are poorly understood inflammatory skin diseases consisting predominantly of macrophages. Granuloma annulare (GA) is the most common granulomatous skin disease and the generalized variant is particularly difficult to treat due to the prolonged course and lack of efficacious treatment options. Necrobiosis lipoidica (NL) is another granulomatous disorder of uncertain etiology. There is a growing body of evidence for the use of Janus kinase (JAK) inhibitors in the management of inflammatory skin diseases. In our report, we describe three patients with recalcitrant granulomatous disease including NL and generalized GA who responded favourably to treatment with the JAK inhibitor tofacitinib. JAK inhibitors may be a beneficial therapeutic option for patients with granulomatous skin diseases that are unresponsive to conventional therapies. Further research is required to determine the long-term efficacy and safety of JAK inhibitors in treating granulomatous skin conditions.

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Effects of TNFα receptor TNF-Rp55- or TNF-Rp75- deficiency on corneal neovascularization and lymphangiogenesis in the mouse

PLoS ONE ◽

10.1371/journal.pone.0245143 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0245143

Author(s):

Anna-Karina B. Maier ◽

Nadine Reichhart ◽

Johannes Gonnermann ◽

Norbert Kociok ◽

Aline I. Riechardt ◽

...

Keyword(s):

Mouse Model ◽

Mrna Expression ◽

Lymphatic Vessels ◽

Corneal Neovascularization ◽

Wild Type ◽

Delayed Effect ◽

Corneal Inflammation ◽

Tnf Α ◽

Mrna And Protein Expression

Tumor necrosis factor (TNF)α is an inflammatory cytokine likely to be involved in the process of corneal inflammation and neovascularization. In the present study we evaluate the role of the two receptors, TNF-receptor (TNF-R)p55 and TNF-Rp75, in the mouse model of suture-induced corneal neovascularization and lymphangiogenesis. Corneal neovascularization and lymphangiogenesis were induced by three 11–0 intrastromal corneal sutures in wild-type (WT) C57BL/6J mice and TNF-Rp55-deficient (TNF-Rp55d) and TNF-Rp75-deficient (TNF-Rp75d) mice. The mRNA expression of VEGF-A, VEGF-C, Lyve-1 and TNFα and its receptors was quantified by qPCR. The area covered with blood- or lymphatic vessels, respectively, was analyzed by immunohistochemistry of corneal flatmounts. Expression and localization of TNFα and its receptors was assessed by immunohistochemistry of sagittal sections and Western Blot. Both receptors are expressed in the murine cornea and are not differentially regulated by the genetic alteration. Both TNF-Rp55d and TNF-Rp75d mice showed a decrease in vascularized area compared to wild-type mice 14 days after suture treatment. After 21 days there were no differences detectable between the groups. The number of VEGF-A-expressing macrophages did not differ when comparing WT to TNF-Rp55d and TNF-Rp75d. The mRNA expression of lymphangiogenic markers VEGF-C or LYVE-1 does not increase after suture in all 3 groups and lymphangiogenesis showed a delayed effect only for TNF-Rp75d. TNFα mRNA and protein expression increased after suture treatment but showed no difference between the three groups. In the suture-induced mouse model, TNFα and its ligands TNF-Rp55 and TNF-Rp75 do not play a significant role in the pathogenesis of neovascularisation and lymphangiogenesis.

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Cnicin from Centaurea benedicta L. is an active compound against skin inflammation in a mouse model

10.21203/rs.3.rs-1124507/v1 ◽

2021 ◽

Author(s):

Orlando Vieira Sousa ◽

Guilherme C. Gonçalves ◽

Lucas S. Queiroz ◽

Everton A. Ferreira ◽

Bruna C. S. Santos ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mouse Model ◽

Skin Inflammation ◽

Cyclooxygenase 1 ◽

Tnf Α ◽

Inflammatory Processes ◽

Anti Inflammatory ◽

Factor Α ◽

Oxide Synthase

Abstract Centaurea benedicta L., commonly known as “cardo santo,” is used as a tonic, antidepressant, anti-inflammatory, antibacterial, and antiseptic in traditional medicine. This study evaluated the topical anti-inflammatory potential of an extract (ECB) and cnicin (CNI) from C. benedicta leaves in a mouse model. Activity was assessed using the ear edema method with croton oil, phenol, capsaicin, and histamine as phlogistic agents. Myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), nitric oxide (NO), t umor necrosis factor α (TNF-α), interleukin 6 (IL-6), and histopathology were assessed as markers of edema/inflammation. Interaction profiles between CNI and cyclooxygenase-1 and -2, induced nitric oxide synthase, and glucocorticoid receptor were examined with molecular docking. Twenty-four h after induction of inflammation, ECB and CNI treatments decreased the thickness and weight of ears by 39.59%– 94.72%. MPO, NAG, NO, TNF-α, and IL-6 levels were also reduced. Histopathological, treatments reduced edema thickness, leukocytes, and vasodilation. Inflammation induced by phenol and histamine was inhibited by ECB and CNI, and ECB suppressed capsaicin-induced inflammation. CNI interacts with cyclooxygenase-1 and nitric oxide synthase through conventional hydrogen bonds, indicating inhibition of these enzymes. ECB and its compound cnicin reduce chemically-induced inflammation in mice suggesting new possibilities for the treatment of diseases associated with dermal inflammatory processes.

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The Role of Gut Microbiome in Psoriasis: Oral Administration of Staphylococcus aureus and Streptococcus danieliae Exacerbates Skin Inflammation of Imiquimod-Induced Psoriasis-Like Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21093303 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3303 ◽

Cited By ~ 1

Author(s):

Karin Okada ◽

Yoshiaki Matsushima ◽

Kento Mizutani ◽

Keiichi Yamanaka

Keyword(s):

Gut Microbiome ◽

Skin Diseases ◽

Skin Inflammation ◽

Gut Bacteria ◽

Rrna Gene ◽

Skin Microbiome ◽

Inflammatory Skin Diseases ◽

Fecal Microbiome ◽

Tnf Α ◽

Inflammatory Skin

Psoriasis is one of the common chronic inflammatory skin diseases in which inflammatory cytokines such as IL-17 and TNF-α play critical roles. Skin microbiome of psoriasis patients is reported to have elevated Staphylococcus and Streptococcus genus. There are controversial reports about gut microbiome of psoriasis patients, and whether the diversity of bacteria in genus level is decreased or not is still unclear. Moreover, it is not yet known if these gut bacteria would be the cause of the inflammation or the result of the inflammation. We analyzed the gut microbiome of the inflammatory skin model mouse (keratinocyte-specific caspase-1 transgenic (Kcasp1Tg) mouse), by analyzing the 16S rRNA gene. Staphylocuccus aureus and Streptococcus danieliae were abundant in Kcasp1Tg mouse fecal microbiome. These dominant bacteria as well as recessive control bacteria were orally administrated to antibiotic-treated wild type mice, and set up imiquimod-induced psoriasis-like skin inflammation model. The skin inflammation including ear thickness and histopathological findings was analyzed. The exacerbated skin lesions with the elevated levels of TNF-α, IL-17A, IL-17F, and IL-22 were observed in Staphylocuccus aureus and Streptococcus danieliae administrated groups. Our finding suggests that there is affinity between skin inflammation severity and certain gut bacteria leading to a vicious cycle: skin inflammation populates certain gut bacteria which itself worsens the skin inflammation. This is the first report on Staphylocuccus aureus and Streptococcuus danieliae effects in vivo. Not only treating the skin lesion but also treating the gut microbiome could be the future key treatment for inflammatory skin disease such as psoriasis.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21103620 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3620 ◽

Cited By ~ 2

Author(s):

Kento Mizutani ◽

Kana Isono ◽

Yoshiaki Matsushima ◽

Karin Okada ◽

Ai Umaoka ◽

...

Keyword(s):

Blood Flow ◽

Bone Density ◽

Mouse Model ◽

Skin Disease ◽

Bone Structure ◽

Skin Inflammation ◽

Inflammatory Skin Disease ◽

Inflammatory Skin ◽

Skin Conditions ◽

The Impact

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 microRNA-let-7b-mediated attenuated strain of influenza A (H1N1) virus in a mouse model

The Journal of Infection in Developing Countries ◽

10.3855/jidc.6861 ◽

2016 ◽

Vol 10 (09) ◽

pp. 973-981 ◽

Cited By ~ 4

Author(s):

Mingming Tan ◽

Wenkui Sun ◽

Chunlai Feng ◽

Di Xia ◽

Xiaoyue Shen ◽

...

Keyword(s):

Mouse Model ◽

Influenza A ◽

Animal Studies ◽

H1n1 Virus ◽

Lethal Dose ◽

Influenza Viruses ◽

Wild Type Virus ◽

Wild Type ◽

Tnf Α ◽

Influenza A H1n1

Introduction: Evaluating the attenuation of influenza viruses in animal studies is important in developing safe and effective vaccines. This study aimed to demonstrate that the microRNA (miRNA)-let-7b-mediated attenuated influenza viruses (miRT-H1N1) are sufficiently attenuated and safe in mice. Methodology: The pathogenicity of the miRT-H1N1virus was investigated in a mouse model, evaluated with median lethal dose (LD50). The replicative dynamics of the miRT-H1N1, wild type (wt)-H1N1, and scramble (scbl)-H1N1 viruses in the lungs of infected mice were compared. The degrees of lesions and the expression levels of IL-6, TNF-α, and IFN-β in the lungs of mice infected with different viruses were also analyzed. Results: In miRT-H1N1 virus-infected mice, 100% of mice survived, and a lower pathogenicity was characterized with non-significant weight loss when compared to mice infected with the control wt virus. The miRT-H1N1 virus was not fatal for mice, even at the highest dose administered. The viral load in the lungs of miRT-H1N1-infected mice was significantly lower than that of the wild-type virus-infected mice. Fewer pulmonary lesions and lower levels of selected pro-inflammatory cytokines in the lungs of the mice infected with the miRT-H1N1 virus were also observed. The virulence of the miRT-H1N1 virus reduced significantly, suggesting that the miRT-H1N1 virus was safe for mice. Conclusions: Our study demonstrated that the miRNA-mediated gene silencing is an alternative approach to attenuating the pathogenicity of wt influenza viruses that have potential in the development of influenza vaccines.

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

Biomedicines ◽

10.3390/biomedicines8090293 ◽

2020 ◽

Vol 8 (9) ◽

pp. 293

Author(s):

Ai Umaoka ◽

Hiroki Takeuchi ◽

Kento Mizutani ◽

Naohiro Seo ◽

Yoshiaki Matsushima ◽

...

Keyword(s):

Mouse Model ◽

Male Infertility ◽

Inflammatory Cytokines ◽

Sperm Count ◽

Skin Inflammation ◽

Testicular Function ◽

Testis Size ◽

Sperm Viability ◽

Wild Type ◽

The Relationship

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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