IL-1F6, IL-1F8 and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control (NN), uninvolved psoriasis (PN) and psoriasis plaque (PP) skin using QRT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2-3 orders of magnitude in PP versus PN skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8 and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8 and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1α and TNF-α induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of anti-microbial peptides and matrix metalloproteins by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of HBD2, HBD3 and CAMP and protein secretion of HBD2 and HBD3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies.

Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasisform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1d following denervation, CD11c+ cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7d and a 30% decrease in CD4+ T cell numbers by 10d. Restoration of SP signaling in denervated KC-Tie2 skin prevented decreases in CD11c+ and CD4+ cells but had no affect on acanthosis; restoration of CGRP signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4+ cells. Under innervated conditions, small molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c+ and CD4+ cell numbers; whereas small molecule inhibition of CGRP resulted in significant reductions in CD4+ cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T cell infiltration and acanthosis and introduce targeting nerve-immunocyte/keratinocyte interactions as potential psoriasis therapeutic treatment strategies.

Patients with psoriasis have systemic and vascular inflammation and are at increased risk for myocardial infarction, stroke, and cardiovascular death. However, the underlying mechanism(s) mediating the link between psoriasis and vascular disease is incompletely defined. This study sought to determine whether chronic skin-specific inflammation has the capacity to promote vascular inflammation and thrombosis. Using the KC-Tie2 doxycycline-repressible (Dox-off) murine model of psoriasiform skin disease, spontaneous aortic root inflammation was observed in 33% of KC-Tie2 compared to 0% of control mice by 12 months of age (P=0.04) and was characterized by the accumulation of macrophages, T-lymphocytes and B-lymphocytes and reduced collagen content and increased elastin breaks. Importantly, aortic inflammation was preceded by increases in serum TNF-α, IL-17A, VEGF, IL-12, MCP-1 and S100A8/A9 as well as splenic and circulating CD11b+Ly-6Chi pro-inflammatory monocytes. Doxycycline treatment of old mice with severe skin disease eliminated skin inflammation and aortic root lesion presence in 1 year old KC-Tie2 animals. Given the bi-directional link between inflammation and thrombosis, arterial thrombosis was assessed in KC-Tie2 and control mice; mean time to occlusive thrombus formation was shortened by 64% (P=0.002) in KC-Tie2 animals; doxycycline treatment returned thrombosis clotting times to control mouse levels (P=0.69). These findings demonstrate that sustained skin-specific inflammation promotes aortic root inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and prothrombotic pathways that produce cardiovascular disease in psoriasis patients.

Summary Background There is ongoing debate regarding the initiation of psoriatic plaque as primarily arising from an anomaly in epidermal keratinocytes (KCs) or from abnormalities in immunocytes that secondarily activate otherwise normal KCs. In mice engineered to overexpress the angiopoietin receptor Tie2 in KCs, skin spontaneously develops the characteristic clinical, histological and immune cell phenotypes of psoriasis which can be reversed with either transgene repression or cyclosporin A administration, suggesting key roles for both KCs and T cells in mediating the skin disease in this murine model. Objectives To determine if antigen presenting cells and macrophages alone are sufficient to sustain psoriasiform inflammation in the KC-Tie2 murine model of psoriasis. Methods Clodronate liposomes were intradermally injected into involved dorsal skin of KC-Tie2 or control animals once a week for 6 weeks and acanthosis, angiogenesis, immune cell infiltration and cytokine production was quantitated using immunohistochemistry and interactive image analyses, enzyme linked immunosorbant assay (ELISAs) and quantitative real-time polymerase chain reaction (qRT-PCR). Results Clodronate liposome injection eliminated CD11c+, F4/80+, and CD11b+ cells in the skin and returned CD8+ T cell numbers to control mouse levels. Antigen presenting cell depletion in KC-Tie2 mouse skin resulted in resolution of the acanthotic skin phenotype, decreased dermal angiogenesis, and a return to control mouse levels for IL-1α, IL-6, IL-23 and TNFα expression and modest reductions in IFNγ and IL-17. Conclusions These findings suggest a critical role for APCs and myeloid cell derived IL-23 and TNFα and underscore the importance of Th1 and Th17 T cells in maintaining the psoriasiform skin phenotype in the KC-Tie2 mouse model.

Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficiency virus (HIV-1) worldwide. HIV-1 load and heterogeneity are increased both locally and systemically in active TB. Mycobacterium tuberculosis (MTB) infection supports HIV-1 replication through dysregulation of host cytokines, chemokines, and their receptors. However the possibility that mycobacterial molecules released from MTB infected macrophages directly interact with CD4+ T cells triggering HIV-1 replication has not been fully explored. We studied the direct effect of different MTB molecules on HIV-1 replication (R5-tropic strain Bal) in anti-CD3- stimulated CD4+ T cells from healthy donors in an antigen presenting cell (APC)-free system. PIM6, a major glycolipid of the mycobacterial cell wall, induced significant increases in the percent of HIV-1 infected T cells and the viral production in culture supernatants. In spite of structural relatedness, none of the other three major MTB cell wall glycolipids had significant impact on HIV-1 replication in T cells. Increased levels of IFN-γ in culture supernatants from cells treated with PIM6 indicate that HIV-1 replication is likely dependent on enhanced T cell activation. In HEK293 cells transfected with TLR2, PIM6 was the strongest TLR2 agonist among the cell wall associated glycolipids tested. PIM6 increased the percentage of HIV infected cells and viral particles in the supernatant in a T-cell-based reporter cell line (JLTRg-R5) transfected with TLR1 and TLR2 but not in the cells transfected with the empty vector (which lack TLR2 expression) confirming that PIM6-induced HIV-1 replication depends at least partially on TLR2 signaling.