Background/Purpose: CX3C chemokine receptor 1 (CX3CR1), a receptor for CX3CL1, has been identified as a key mediator of macrophage migration into injured tissue or inflammation sites. It has recently been reported that serum CX3CL1 levels were significantly elevated in patients with rheumatoid arthritis (RA). Psoriasis is a common skin condition that causes skin redness and irritation. Some patients with psoriasis suffer from arthritis, which is clinically similar to RA, suggesting that both psoriatic arthritis and RA have the same underlying immunological cause. Thus, we hypothesized that CX3CL1 and CX3CR1 also play important roles in the development of psoriasis. To elucidate the role of CX3CL1 and CX3CR1 in a mouse model of psoriasis, psoriasiform skin inflammation triggered by topical application of imiquimod, an agonist of Toll-like receptor (TLR) 7, was assessed in CX3CR1-deficinet mice and wild-type (WT) mice.

Methods: CX3CR1^–/- and WT mice received a daily topical dose of 62.5 mg imiquimod cream (5%) on a shaved back and ears for 6 consecutive days. Erythema, scaling, and skin thickness were independently scored every day. Total RNA was isolated from ears 24 and 48 hours after the start of topical application and mRNA expression levels of cytokines were investigated. Furthermore, macrophages were harvested from peritoneal cavity of naive CX3CR1^–/- and WT mice and cultured in the presence or absence of CX3CL1. Cytokine expression in macrophages was examined at mRNA levels by quantitative RT-PCR and at protein levels using enzyme-linked immunosorbent assay. We also investigated macrophage populations by checking expression of M1 and M2 macrophage markers.

Results:  Imiquimod-induced skin inflammation assessed by erythema, scaling, and skin thickness was milder in CX3CR1^–/- mice than WT mice. In inflamed skin, mRNA expression levels of IL-12/IL-23p40, IL-23p19, IL-12p35, IL-17A, IL-17F, IL-22, IL-1β, IL-6, TNFα, IL-36α, and IL-36γ were significantly decreased in CX3CR1^–/- mice compared to WT mice. The number of macrophages harvested from peritoneal cavity of naive CX3CR1^–/- mice were about one third of that of WT mice. The expression levels of IL-1β, IL-6, TNFα in macrophages of CX3CR1^–/- mice were significantly lower than that of WT mice. Addition of CX3CL1 into the culture media, however, decreased expression of these cytokines in WT macrophages, suggesting that loss of interactions between CX3CL1 and CX3CR1 did not directly cause decrease in cytokine expression. In inflamed skin of CX3CR1^–/- mice, MCP-1 (a M1 macrophage marker) mRNA expression levels were significantly lower, while mRNA levels of MRC-1, Arginase 1, and Ym1/2 (M2 macrophage markers) were significantly higher than in WT mice. Similar findings were observed in peritoneal macrophages, suggesting that difference in macrophage populations was one possible reason for different cytokine expression.

Conclusion: CX3CL1 and CX3CR1 play important roles for infiltration of M1 macrophages both in the skin and peritoneal cavity. Predominance of M2 macrophages in CX3CR1^–/- mice may account for decreased expression of IL-1β, IL-6, and TNFα and milder imiquimod-induced skin inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cx3cr1-deficiency-attenuates-imiquimod-induced-psoriasis-like-skin-inflammation-by-predominant-infiltration-of-m2-macrophages/