Unconjugated bilirubin and its derivative ameliorate IMQ-induced psoriasis-like skin inflammation in mice by inhibiting MMP9 and MAPK pathway

Madeva Bharatha, Manuganahalli B. Nandana, Raju Praveen, Spandan Nayaka, Devadasan Velmurugan, Bannikuppe S. Vishwanath, Rajesh Rajaiah

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Abstract

Psoriasis is a chronic immune-mediated inflammatory skin disease that involves dysregulated proliferation of keratinocytes. Psoriatic skin lesions are characterized by redness, thickness, and scaling. The interleukin axis of IL-23/IL-17 is critically involved in the development of human psoriasis. Imiquimod (IMQ), an agonist of TLR7 is known to induce psoriatic-like skin inflammation in mice. The topical application of IMQ induces systemic inflammation with increased proinflammatory cytokines in serum and secondary lymphoid organs. Further, matrix metalloproteases (MMPs) have been implicated in the pathophysiology of psoriatic-like skin inflammation. The increased MMP9 activity and gene expression of proinflammatory cytokines in IMQ-induced psoriatic skin is mediated by the activation of the MAPK pathway. Moreover, the increased expression of neutrophil-specific chemokines confirmed the infiltration of neutrophils at the site of psoriatic skin inflammation. In contrast, expression of IL-10, an anti-inflammatory cytokine gene expression is reduced in IMQ-treated mice skin. Topical application of unconjugated bilirubin (UCB) and its derivative dimethyl ester of bilirubin (BD1) on IMQ-induced psoriatic mice skin significantly mitigated the symptoms of psoriasis by inhibiting the activity of MMP9. Further, UCB and BD1 reduced neutrophil infiltration as evidenced by decreased myeloperoxidase (MPO) activity and reduced gene expression of proinflammatory cytokines, and neutrophil-specific chemokines. Apart from these modulations UCB and BD1 reduced MAPK phosphorylation and upregulated anti-inflammatory cytokines. To conclude, UCB and BD1 immunomodulated the psoriatic skin inflammation induced by IMQ in mice by inhibiting neutrophil mediated MMP9, decreased proinflammatory cytokines gene expression and modulating the MAPK pathway.

Original languageEnglish (US)
Article number111679
JournalInternational Immunopharmacology
Volume130
DOIs
StatePublished - Mar 30 2024

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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