ABSTRACT
Patient-reported outcome (PRO) measures provide an important perspective on how patients feel and function that cannot be adequately captured by clinical measures. A PRO is any report that comes directly from a patient about a health condition or its treatment without interpretation of the patient's response by a clinician or anyone else.
Subject(s)
Device Approval/standards , Outcome Assessment, Health Care/statistics & numerical data , Patient Satisfaction , United States Food and Drug Administration/trends , Drug Approval/methods , Humans , Quality of Life , Reproducibility of Results , Surveys and Questionnaires , United StatesABSTRACT
Mast cells (MC) are anatomically located near nerves and blood vessels in skin and the gastrointestinal tract and tend to localize within certain cutaneous tumors such as neurofibromas. However, the molecular mechanisms by which MC home to these sites are not well characterized. Fractalkine (FK) is a membrane-bound CX3C chemokine that displays constitutive expression in dendritic cells as well as in non-hematopoietic tissues including mammalian brain. Here we show that FK is constitutively expressed by skin endothelial cells, dermal dendrocytes and cells within neurofibromas. By reverse transcription-PCR, FK receptor, CX3CR1, is expressed by cultured murine bone marrow-derived MC (BMMC) of both connective tissue and mucosal phenotypes. Non-activated human dermal MC isolated from neonatal foreskin similarly demonstrated CX3CR1 expression. In chemotaxis assays, FK attracted MC with maximal migration occurring between 25 - 125 ng / ml. BMMC were not stimulated to release proinflammatory mediators in the presence of FK as measured by granule-associated beta-hexosaminidase release. Thus, CX3CR1 is expressed by MC and effectively mediates chemotaxis without inducing degranulation. We propose that the constitutive expression of FK on certain cells in the skin may be a factor in the tissue-specific homing of MC.
Subject(s)
Cell Degranulation , Chemokines, CX3C , Chemokines, CXC/physiology , Mast Cells/physiology , Membrane Proteins/physiology , Skin/cytology , Animals , CX3C Chemokine Receptor 1 , Cell Adhesion , Chemokine CX3CL1 , Chemokines, CXC/analysis , Chemotaxis , Female , Humans , Membrane Proteins/analysis , Mice , Mice, Inbred BALB C , RNA, Messenger/analysis , Receptors, Cytokine/genetics , Receptors, HIV/geneticsABSTRACT
The lone CX3C chemokine, fractalkine (FK), is expressed in a membrane-bound form on activated endothelial cells and mediates attachment and firm adhesion of T cells, monocytes and NK cells. We now show that FK is associated with dendritic cells (DC) in epidermis and lymphoid organs. In normal human skin, dual-color fluorescence microscopy co-localized FK expression with Langerhans cells expressing CD1a. In tonsil, FK-positive DC expressed CD83, a marker for mature DC. Human and murine cultured DC up-regulated FK mRNA expression with maturation. Furthermore, CD40 ligation, but not TNF-alpha or lipopolysaccharide treatment, of activated, migratory DC that had migrated from skin explants resulted in a 2.5-fold increase of surface expression of FK without significant alterations of expression of CD80, CD86, CD54 or MHC class II. Since FK mediates adhesion of T cells to activated endothelial cells, the increased expression of FK during DC maturation (and particularly by CD40 ligation) may play a role in the ability of T cells and mature DC to form conjugates and engage in cell-cell communication.
