CCN1, a Pro-Inflammatory Factor, Aggravates Psoriasis Skin Lesions by Promoting Keratinocyte Activation

Abstract

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. The pathogenesis of psoriasis is multifactorial and is not fully understood. Here we demonstrate that CCN1 (also called Cyr61, which is short for cysteine-rich 61), an extracellular matrix protein that is also considered a pro-inflammatory factor, is highly expressed in the lesional skin of psoriasis patients, as well as in that of imiquimod (IMQ)- and IL-23-treated psoriasis-like mice. Then we show that blocking CCN1 function in vivo attenuates epidermal hyperplasia and inflammation in psoriasis-like mice. Further, in primary cultured normal human keratinocytes and HaCaT (human keratinocyte cell line) cells, CCN1 promotes keratinocyte activation, including the proliferation and expression of immune-related molecules. Finally, we observe that integrin α6β1 is the receptor of CCN1 in keratinocytes, and CCN1 stimulation activates the downstream phosphoinositide-3 kinase/Akt/NF-κB signaling pathway. Taken together, our findings reveal that CCN1 has a critical role in psoriasis pathogenesis. Moreover, as CCN1 is a secreted extracellular matrix (ECM) protein, our study also provides evidence that ECM, which is involved in psoriatic pathogenesis, could be a potent target for psoriasis treatment.

CCN1 promotes IL-1β production in keratinocytes by activating p38 MAPK signaling in psoriasis

“…In our previous study, we found that CCN1 was highly expressed in the lesional skins of psoriasis patients and was involved in the pathogenesis of psoriasis by promoting keratinocyte activation27. As CCN1 is considered as a pro-inflammatory factor in RA pathology, we further explored whether CCN1 contributed to the inflammation of psoriasis.…”

“…In our previous report, we demonstrated that CCN1 promoted KC activation through the integrin receptor α6β127. To determine whether CCN1 stimulated IL-1β expression by binding to α6β1, we silenced α6β1 production by siRNA.…”

“…CCN1 regulates cell proliferation, migration, adhesion, angiogenesis, tumorigenesis and inflammation22232425. CCN1 exerts its multiple functions predominantly by binding to various integrin receptors, leading to the activation of downstream signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways22242627. CCN1 has been shown to enhance the synovium hyperplasia and inflammation involved in RA24262829.…”

“…CCN1 has been shown to enhance the synovium hyperplasia and inflammation involved in RA24262829. Interestingly, we reported that CCN1 was up-regulated in psoriatic skin lesions and promoted keratinocyte (KC) proliferation and activation via the α6β1/PI3K/Akt/NF-κB pathway in psoriasis, indicating that CCN1 was involved in the development and pathogenesis of psoriasis2730. However, the role of CCN1 in regulating inflammation in psoriasis is still unclear.…”

The profile of Cyr61 expression data correlate to the skin inflammation in psoriasis

“…Mice received intraperitoneal injections of 200 μg/day of either anti-Cyr61 mAb 093G9 or control IgG1 (Millipore, Billerica, MA, USA) 2 days after IMQ treatment. After16 days later mice were sacrificed and skin samples were collected and inspected [4].…”