Fibrocytes: emerging effector cells in chronic inflammation
Highlights
► Fibrocytes are bone marrow derived cells that are implicated in tissue remodeling. ► Fibrocytes demonstrate marked phenotypic plasticity in response to local cues. ► Fibrocytes secrete cytokines and present antigen in response to inflammatory stimuli. ► Fibrocytes secrete extracellular matrix components in response to TH2 cytokines. ► Fibrocytes may serve as biomarkers and/or therapeutic targets in chronic inflammatory disease.
Introduction
Chronic inflammatory responses are characterized by replacement of normal organ structure with inflammatory cells and excess connective tissue. This pathology is seen in the setting of persistent injury that causes ongoing immune activation and impeded repair. It was until recently believed that normal and dysregulated repair responses result from the recruitment, proliferation, and activation of local connective tissue cells such as fibroblasts [1]. However, an expanding body of research now supports the involvement of bone marrow derived progenitor cells called fibrocytes in these processes. These cells are believed to originate from a monocyte derived precursor and are implicated in the pathogenesis of many chronic inflammatory states including those involving the lung [2], autoimmunity [3••, 4, 5, 6], liver [7••], skin [8], and even normal aging [5]. In the last year alone there has been an explosion of data regarding the pathways regulating fibrocyte differentiation and phenotype. This review will discuss the current criteria for fibrocyte identification in the circulation and tissue, present the most recent data regarding their differentiation pathways and known functions, highlight recent literature regarding the role of fibrocytes in chronic inflammatory diseases affecting the lung, liver, autoimmunity, and aging, and will conclude by suggesting areas for further study.
Section snippets
Identification of fibrocytes
Identification of fibrocytes in the circulation or diseased organs involves co-detection of characteristic cell surface proteins and collagens or extracellular matrix components (ECM) [9]. The hematopoietic origin of human fibrocytes is reflected by their expression of CD45 and Leukocyte specific protein-1 (LSP-1) [10]. Their presumed monocyte origin is reflected by expression of CD11b, CD11c, and CD11d [10]. Their role in immunologic responses is reflected by their expression of chemokine
Fibrocyte origin and differentiation
Human fibrocyte precursors co-purify with CD14+ monocytes [4]. Murine modeling shows that fibrocyte outgrowth from monocytes is enhanced by enrichment for CD11b, CD115, and Gr1 [17]. These effects are require direct contact with activated CD4+ lymphocytes and occur via an mTOR-PI3 kinase dependent pathway [17]. Fibrocyte differentiation is also regulated by the Fcγ receptors CD64 and CD32 [18]. Inhibition of these receptors with Serum Amyloid P attenuates fibrocyte accumulation in human [19]
Fibrocyte homing
Murine fibrocytes express a several chemokine receptors including CCR1, CCR2 [7••, 11], CCR7, and CXCR4 which in several studies have been shown to control migration and recruitment of fibrocytes to injured tissue [12, 29]. Human fibrocytes also express the chemokine receptors CCR2 [11], CCR3, and CCR5 [30] CXCR4 [12], as well as the β1 integrin subunit and Semaphorin 7a [25]. One study found an association between concentrations of soluble factors such as TNF, IL-10, MCP-1 and IL-1 receptor
Fibrocyte function
While a definite contribution to disease pathogenesis is lacking, fibrocytes display many functions that could influence chronic inflammatory responses. Early studies of fibrocyte biology centered on their role as a circulating source of contractile myofibroblasts. However, because lineage tracing studies show only minimal contribution of fibrocytes to α-SMA production in several models [32, 33] it is likely that fibrocytes possess other properties that promote tissue remodeling. Thus it is
Fibrocyte associations with chronic inflammatory disease
Given the combination of ongoing inflammation and fibroblast-driven end-organ remodeling seen in chronic inflammatory disease, fibrocytes have emerged as a novel area of investigation in this area. Because the most recent studies of fibrocytes have focused on lung, automimmunity, liver, and normal aging, information regarding fibrocytes in these disorders is summarized below.
Aging
Dysregulated immune responses are seen in otherwise healthy, aged individuals. While the factors regulating this phenotype remain unclear, recent studies suggest a role for fibrocytes. Murine modeling using the senescence-accelerated mice shows increased circulating and intrapulmonary fibrocytes, which may at least partially explain the increased sensitivity to bleomycin seen in these mice [46]. Similarly, imaging studies using the Col-1-luciferase mouse described above show increased egress of
Conclusions
Fibrocytes may serve as novel targets for intervention in chronic inflammatory disease. However, development of fibrocyte based-therapies requires better understanding of their function. Thus, development of modeling systems allowing better characterization of antigen presentation, production of soluble mediators, and tissue remodeling are sorely needed. In addition, owing to the considerable overlap in cell surface markers shared by fibrocytes, monocytes, and fibroblasts, development of
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Sources of support: NIH (R01 HL109033), Scleroderma Foundation, and a joint research award from the American Thoracic Society and Pulmonary Fibrosis Foundation (all to ELH).
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