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

Abstract

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.

IL-17A Is the Critical Cytokine for Liver and Spleen Amyloidosis in Inflammatory Skin Disease

“…Persistent refractory dermatitis can lead to organ amyloidosis [ 3 , 4 , 5 ]. A large amount of cytokines released from the involved area of persistent inflammation may be mixed in the bloodstream, causing the liver to produce amyloid A protein.…”

“…Acute phase SAA has several functions, such as the recruitment of immune cells to the inflammation sites and transport of cholesterol to the liver. Among the SAAs, SAA3 is produced in the skin, and although SAA3 is highly concentrated in the skin, its concentration in the blood did not increase in inflammatory mice, while SAA1 and SAA2 mainly produced in the liver are predominantly increased in inflammatory mouse plasma and are deposited in organs [ 4 ].…”

“…Eight-week-old female KCASP1Tg and WT littermate mice were orally treated with the selective JAK1 and JAK2 inhibitor baricitinib (OYC1, Oriental Yeast, Kyoto, Japan) or an orally active multi-targeted tyrosine kinase inhibitor, especially JAK1, JAK2, JAK3, and TYK2 cerdulatinib hydrochloride (Astellas, Tokyo, Japan). The treatment schedule was as follows: 5 mg/kg baricitinib or 5 mg/kg cerdulatinib was administered every day, as previously reported [ 4 , 9 ]. All mice were sacrificed at 16 weeks of age, and the livers and spleens were analyzed.…”

“…Psoriasis and atopic dermatitis are chronic and intractable inflammatory skin diseases, and skin inflammation may be associated with amyloid deposition [ 3 , 4 , 5 ]. Primary localized cutaneous amyloidosis, such as lichen amyloidosis, is characterized by severely itchy, scaly, and reddish patches of thickened skin with multiple small bumps.…”

“…These will likely be deposited in many distant organs. The deposition of SAA1 and SAA2 has been detected in the gastrointestinal tract, resulting in hypoalbuminemia due to albumin leakage [ 4 ]. The amyloid deposition was also detected in the kidneys and spleen, resulting in organ collapse at the late phase [ 3 , 12 ].…”