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

Abstract

Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.

Immunoproteasome inhibition attenuates experimental psoriasis

“…Cutaneous inflammation is not a problem solely related to skin, but the release of several inflammatory products into systemic circulation can affect other organs resulting in comorbidities ( 48 ). Interestingly, IL-17A is responsible for the formation of amyloidosis in both the liver and the spleen ( 49 ), a disorder in which abnormal proteins accumulate. Additionally, IL-17-related cytokines play an important function in the formation of microabscesses by neutrophils through “connection to IκB kinase and stress-activated protein kinases” signaling into the keratinocytes ( 50 ).…”

The Interplay of Type 1, Type 2, and Type 3 Lymphocytes and Cytokines in Atopic Dermatitis

“…Cutaneous inflammation is not only a localized problem of the skin but also causes inflammation of organs throughout the body, resulting in comorbidities and a shortened life expectancy. Overproduction of skin-derived inflammatory cytokines results in organ failures, such as cardiovascular and cerebrovascular disorders [ 12 , 13 ] and systemic amyloidosis [ 13 , 14 , 15 , 16 , 17 ]. Many cytokines released from active skin lesions of persistent inflammation may be mixed in the bloodstream, causing the liver to produce amyloid A protein.…”

“…This immune response peaked in the acute phase at 4 months of age and decreased later on in the chronic phase at 6 months of age. Previous studies have suggested that the spleen, which is involved in lymphocyte maturation, may be immunosuppressive in the chronic phase owing to the destruction of the lymph follicle architecture caused by amyloid deposition, possibly leading to decreased lymphocyte biosynthesis [ 13 , 16 ]. In helper T cells, the number of type 2 and type 3 cytokine-producing cells was higher than that of ILCs, suggesting a greater diversity of selection.…”

New treatment of pyoderma gangrenosum and hidradenitis suppurativa: A review

“…Early diagnosis and intervention for PG and HS are crucial, not only to ensure effective treatment and enhance the patient's quality of life but also to counteract systemic inflammation, a phenomenon observed in conditions such as psoriasis and atopic dermatitis. While direct evidence for such systemic effects remains elusive in the context of PG and HS, the activation of white blood cells and ensuing cutaneous inflammation could potentially herald complications in the cardiovascular system and other organs 83–91 . Given these potential risks, it is imperative to recognize the value of timely deployment of potent treatments, such as biologics and small molecules, to mitigate inflammation.…”