The pro-inflammatory S100A8/9 heterodimer activates immune cells and vascular endothelium, leadingto increased leukocyte traffic into psoriatic tissue. Increased leukocyte trafficking in psoriasis results inmonocyte infiltration from the blood, macrophage and myeloid dendritic cell differentiation, and increased Tcell activation. Upon T cell activation, TNFcc produced by myeloid monocytic cells is increased therebymediating psoriasis skin changes. We hypothesize that S100A8/A9 acting as a damage associatedmolecular pattern molecule (DAMP) recruits, activates and differentiates monocytes into psoriaticskin. We further predict that blocking A8/A9 activity or macrophage recruitment to the uninvolvedtissue will block the development of the psoriasis phenotype. Given the unique presence of lining macrophages in psoriatic tissue, this proposal seeks to addresswhether the accumulation and/or activation of macrophages in psoriatic skin is pathogenic and if this isdependent upon S100A8/A9 levels. The function of 'lining macrophages' and the state of differentiation ofthese particular macrophages is of particular interest, as these cells are in juxtaposition not only to T cellsarriving from endothelial venules, but also to basal keratinocytes lining the DEJ. We will determine whetherS100 proteins mediate activation or differentiation of the spectrum of myeloid monocytic cells (activatedmonocytes, DC, macrophages) in lesional skin, and if macrophages are necessary for the development ofpsoriatic lesions using a xenogenic transplant model. We propose the following specific aims:
Aim I : Todetermine whether myeloid monocytic cells in psoriasis skin are activated to an inflammatory state and/ordifferentiated to macrophages (DEJ lining or vascular) and the role of S100A8/A9 heterodimer in thisprocess.
Aim II : Todefine the role of macrophages and S100A8/A9 in a clinicalpsoriasis response, and ina murine xenogenic transplant model of psoriasis. The interplay of T cell cytokines with monocyte/macrophage cytokines and chemokines and the apparentdirect effect on keratinocytes suggests a combined pathology that ultimately results in signals that, togetherwith genetic susceptibility, lead to active psoriasis. Interference (i.e., elimination) with any one cellularcomponent of this triad in disease is (and has been) likely to lead to clinical improvement. Therefore,understanding the relationship between these cell types as well as the importance of each component andpotential mechanism(s) of action, are critical to increasing our likelihood of developing therapeutic modalitiesthat address the totality of psoriasis.
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