FcγRIIB inhibits inflammation in a murine model of psoriasis.

BACKGROUND: Psoriasis is a chronic, inflammatory cutaneous disease. FcγRIIB is a low-affinity receptor for the IgG Fc fragment that provides a negative feedback pathway to down-regulate B-cell antigen receptor signaling. OBJECTIVE: The aim of this study was to investigate the role of FcγRIIB in the development of murine imiquimod (IMQ)-induced, psoriasis-like skin inflammation. METHODS: The experimental psoriasis-like skin inflammation was induced by the topical application of IMQ to the ears of FcγRIIB deficient (FcγRIIB-/-) and wild-type (WT) mice. After 6 days, epidermal thickness and inflammatory cell infiltration of the skin were histopathologically assessed and cytokine and chemokine expression levels were measured with RT-PCR. RESULTS: Skin inflammation was significantly worse in FcγRIIB-/- mice than WT mice. In the skin, the numbers of Gr-1+ neutrophils, CD11c+ dendritic cells, and Foxp3+ T cells were significantly higher in FcγRIIB-/- mice than WT mice. In the spleen, the numbers of CD25+Foxp3+ T cells and CD19+IL-10+ B cells were also significantly higher in FcγRIIB-/-mice than WT mice. The mRNA expression of Il-6, Il-17a, and Il-23a was significantly enhanced in FcγRIIB-/- mice. An adoptive transfer of splenic leukocytes from FcγRIIB-/- mice into WT mice also exacerbated skin inflammation compared to WT mice that received splenic leukocytes from WT mice. Intravenous immunoglobulin significantly reduced skin inflammation in WT mice, but this improvement was not observed in FcγRIIB-/- mice. CONCLUSION: These results indicate that FcγRIIB likely plays a suppressive role in IMQ-induced, psoriasis-like skin inflammation. Furthermore, signal modulation via FcγRIIB is a potential therapeutic target for psoriasis.

Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma.

BACKGROUND: Janus kinase (JAK)-signal transducer and activator of transcription (STAT) was hyperactivated in biopsies from patients with systemic sclerosis (SSc) and in several autoimmune disease models. Tofacitinib, a pan-JAK inhibitor, blocks the downstream signaling of multiple cytokines and has exhibited therapeutic efficacy in various autoimmune diseases, although its immunomodulating property in scleroderma is unclear. OBJECTIVE: To evaluate the effect of tofacitinib on the modulation of cytokine-producing T and B cells, and proinflammatory cells in a mouse model of SSc. METHODS: Bleomycin (BLM)-induced SSc was generated by intradermal injection of BLM or PBS for control. Mice received intraperitoneal tofacitinib (20 mg/kg) or vehicle 3 times per week from day 0-28. Mice were sacrificed at day 28 after the last BLM/PBS injection. RESULTS: Tofacitinib administration significantly alleviated fibrosis of the skin and lungs in scleroderma mouse model. Furthermore, tofacitinib suppressed adaptive and innate immune responses by reducing splenocytes, total lymphocytes, CD4+ T helper cells (especially Th2 and Th17 subtypes), IL-6-producing effector B cells, PDCA-1+ dendritic cells in the spleen, and infiltration of F4/80+, CD206+ and CD163+ macrophages in the skin and lungs. Conversely, tofacitinib increased the proportions of splenic regulatory T and B cells. The mRNA expression of extracellular matrix proteins and fibrogenic cytokines was downregulated by tofacitinib in both the skin and lungs. CONCLUSION: These observations suggest JAK inhibition as a therapeutic approach for the treatment of inflammatory and fibrotic diseases, and highlight the potential of tofacitinib as a promising candidate for treating patients with scleroderma.