Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

Abstract

Significance We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

“…This model depicts the inflammatory phase of PsA, where macrophages, γδ T cells and IL-17A are the major contributors. Treatment with clodronate liposomes, anti-Ly6G and the neutralization of IL-17A and TNFα either completely blocked or significantly attenuated both joint and skin inflammation [63]. …”

“…In addition, IL-17 may also promote monocyte adhesion by inducing molecules such as ICAM-1, integrin α4, platelet/endothelial cell adhesion molecule 1 and CD99. M1 macrophages have a key function in both acute and chronic skin inflammation in animal models of Ps and PsA (the IKK, PL/J CD18 β2 and mannan-induced Ps/PsA models), where macrophage depletion leads to resolution of skin inflammation [63,78,79]. Psoriatic skin contains a large number of macrophage-secreting proinflammatory cytokines (IL-6, IL-12 and IL-23) [80,81].…”

18F-Labeling of Mannan for Inflammation Research with Positron Emission Tomography

“…3−6 Recently, we have generated a new psoriasis and psoriatic arthritis mouse model. 7 After being administrated with a single dose of mannan from Saccharomyces cerevisiae (S. cerevisiae), mice develop an acute inflammation in skin and articular joints. The disease phenotypes resemble the human psoriasis and psoriatic arthritis, which has implications in clinical inflammation research.…”

“…In the original studies, mannan (10 mg per mouse) was intraperitoneally injected into mice to induce psoriasis and psoriatic arthritis. 7 To perform the biological evaluations in similar experimental settings, [ 19 F]fluoromannan (10 mg per mouse) was injected intraperitoneally into mice with a neutrophil cytosolic factor 1 gene mutation (Ncf1 m1J/m1J ), 7 and mannan (10 mg per mouse) was administrated into control mice for comparison. The disease phenotypes were followed by visual observation, and the disease severity was quantified by blinded scoring.…”

Reactive oxygen homeostasis – the balance for preventing autoimmunity

“…Evidence for the latter comes from association of ROS-deficiency with severe chronic inflammation in animal models and human patients in an ever growing number of pathologic conditions. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] In this review we want to illustrate how ROS are produced, what targets they modify, and how they influence various immune cell types. We further want to elaborate on how the ROS (im)balance influences the initiation, onset, and pathogenesis of several autoimmune diseases.…”