Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8⁺ T-cell memory in wild-type and humanized mice

Abstract

Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms. Methods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed. Results: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8 + central memory T (T CM ) and CD8 + resident memory T (T RM ) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8 + , but not CD4 + , subset of CD44 high CD62L high T CM in psoriatic mice, whereas methotrexate (MTX) lowered CD4 + , but not CD8 + , T CM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8 + T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8 + CLA + , CD8 + CD69 + or CD8 + CD103 + T RM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8 + , but not CD4 + , T CM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8 + T CM and CD103 + T RM cells in humanized mice. Conclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8 + T-cells.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

“…There is a growing appreciation that the activity of the nervous system plays an active role in various skin diseases, including psoriasis 5 , 7 , 8 , 11 , 12 , 50 . However, most of the emerging therapies exclusively target immune signaling with various anti-inflammatory drugs 54 , 55 and monoclonal antibodies against single pro-inflammatory cytokines 56 . Monoclonal antibodies have greatly advanced the clinical management of psoriasis, but not all patients are responsive to these treatments that can be expensive over prolonged periods, lead to unwanted effects such as immunosuppression, and occasionally even aggravate the disease 57 , 58 .…”

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

“…However, in terms of immunomodulatory effects of ARTs, tremendous progress has been made during the last five to six years. We have recently demonstrated that dihydroartemisinin, an artemisinin derivative, ameliorates psoriatic skin inflammation and its relapse by selectively diminishing memory CD8+ T cells ( 11 ). In this review, we summarize recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and allograft rejection as well as the mechanisms underlying their actions.…”

Metabolomic profiling reveals amino acid and carnitine alterations as metabolic signatures in psoriasis

“…IMQ, a ligand of TLR-7/8, induces psoriasis-like dermatitis in mouse mimicking human psoriasis pathogenesis and systemic inflammation, including elevated levels of IL-23/IL-17A-Th17 axis pro-inflammatory cytokines and chemokines 34 - 36 . We analyzed the amino acid profiles in the IMQ-induced psoriasis-like dermatitis mouse model by amino acid-targeted metabolomics.…”