A Chronic Psoriasis Model Using Long-Term Imiquimod Application in IL-10-Deficient Mice: Recapitulating Skin Inflammation, Comorbidities, and Gut–Skin Axis Alterations
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Background: Psoriasis is a persistent systemic inflammatory condition mediated by the inter- leukin (IL)-23/IL-17 signaling pathway. Existing murine models, including imiquimod (IMQ)- applied wild-type (WT) mice, may not reflect chronicity and systemic comorbidities of psoriasis, particularly gut-related manifestations linked to the gut–skin axis. Objective: To establish a murine model that more accurately reflects chronic psoriasis, its sys- temic comorbidities, and associated gut environment alterations. Methods: C57BL/6 IL-10-deficient (IL-10 knockout [KO]) and WT mice received topical IMQ or vehicle for 6 weeks. Subsequently, tissue samples from skin, colon, joints, kidneys, liver, abdom- inal aortas, lymph nodes, and spleens, as well as fecal and blood samples, were collected for histopathologic, immunologic, gut environment analysis. Results: IMQ-treated IL-10 KO mice developed prolonged psoriatic inflammatory responses with increased epidermal thickness and higher infiltration of CD45+, myeloperoxidase+, and IL-17+ cells. They also exhibited early-onset, severe colitis with marked weight loss, shortened colon length, and elevated colitis severity scores. While IMQ induced systemic inflammation in multiple organs, IL-10 KO mice did not show more severe joint, liver, or kidney involvement than WT mice. Elevated serum tumor necrosis factor alpha and plasminogen activator inhib- itor-1 levels, increased heart/body weight ratio, enhanced gut permeability, and distinct gut microbiota profiles were observed in IL-10 KO mice. Conclusion: The 6-week IMQ-applied IL-10 KO model may better reflect chronic and severe pso- riasis with gut-related comorbidities, offering a valuable platform to investigate the gut–skin axis.
Abstract
Background: Psoriasis is a persistent systemic inflammatory condition mediated by the inter- leukin (IL)-23/IL-17 signaling pathway. Existing murine models, including imiquimod (IMQ)- applied wild-type (WT) mice, may not reflect chronicity and systemic comorbidities of psoriasis, particularly gut-related manifestations linked to the gut–skin axis. Objective: To establish a murine model that more accurately reflects chronic psoriasis, its sys- temic comorbidities, and associated gut environment alterations. Methods: C57BL/6 IL-10-deficient (IL-10 knockout [KO]) and WT mice received topical IMQ or vehicle for 6 weeks. Subsequently, tissue samples from skin, colon, joints, kidneys, liver, abdom- inal aortas, lymph nodes, and spleens, as well as fecal and blood samples, were collected for histopathologic, immunologic, gut environment analysis. Results: IMQ-treated IL-10 KO mice developed prolonged psoriatic inflammatory responses with increased epidermal thickness and higher infiltration of CD45+, myeloperoxidase+, and IL-17+ cells. They also exhibited early-onset, severe colitis with marked weight loss, shortened colon length, and elevated colitis severity scores. While IMQ induced systemic inflammation in multiple organs, IL-10 KO mice did not show more severe joint, liver, or kidney involvement than WT mice. Elevated serum tumor necrosis factor alpha and plasminogen activator inhib- itor-1 levels, increased heart/body weight ratio, enhanced gut permeability, and distinct gut microbiota profiles were observed in IL-10 KO mice. Conclusion: The 6-week IMQ-applied IL-10 KO model may better reflect chronic and severe pso- riasis with gut-related comorbidities, offering a valuable platform to investigate the gut–skin axis.