Fibrocytes: emerging effector cells in chronic inflammation

https://doi.org/10.1016/j.coph.2012.03.002Get rights and content

Fibrocytes are unique cells possessing the proinflammatory properties of macrophages and the tissue remodeling properties of fibroblasts. Because these cells display a strong association with many human diseases characterized by chronic and dysregulated inflammatory responses the study of fibrocytes is important and timely. This review presents recent data regarding fibrocyte origin, identification, differentiation, and appearance in diseased tissue. The available data regarding the association of fibrocytes with several forms of chronic tissue inflammation seen in the setting of lung disease, autoimmunity, liver disease, and normal aging will be presented. This review concludes by putting these data in perspective and by suggesting future areas of investigation. It is hoped that this information will lead to additional investigations in this burgeoning field and improve our understanding of the novel role fibrocytes may play in human disease.

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).

References (46)

  • Y. Gan et al.

    Role of Semaphorin 7a in TGF b1 induced lung fibrosis, and scleroderma-related interstitial lung disease

    Arth Rheum

    (2011)
  • X. Peng et al.

    Local apoptosis promotes collagen production by monocyte-derived cells in transforming growth factor beta1-induced lung fibrosis

    Fibrogenesis Tissue Repair

    (2011)
  • S.K. Mathai et al.

    Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype

    Lab Invest

    (2010)
  • D. Scholten et al.

    Migration of fibrocytes in fibrogenic liver injury

    Am J Pathol

    (2011)
  • R.A. Reilkoff et al.

    Fibrocytes: emerging effector cells in chronic inflammation

    Nat Rev Immunol

    (2011)
  • D. Pilling et al.

    Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts

    PLoS ONE

    (2009)
  • J.E. Ekert et al.

    Chemokine (C-C motif) ligand 2 mediates direct and indirect fibrotic responses in human and murine cultured fibrocytes

    Fibrogenesis Tissue Repair

    (2012)
  • B. Mehrad et al.

    Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis

    Int J Biochem Cell Biol

    (2009)
  • T. Kisseleva et al.

    Fibrocyte-like cells recruited to the spleen support innate and adaptive immune responses to acute injury or infection

    J Mol Med (Berl)

    (2012)
  • L. Bianchetti et al.

    Extracellular matrix remodelling properties of human fibrocytes

    J Cell Mol Med

    (2012)
  • S.J. Curnow et al.

    Distinct types of fibrocyte can differentiate from mononuclear cells in the presence and absence of serum

    PLoS ONE

    (2010)
  • M. Niedermeier et al.

    CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes

    Proc Natl Acad Sci USA

    (2009)
  • D. Pilling et al.

    Aggregated IgG inhibits the differentiation of human fibrocytes

    J Leukoc Biol

    (2006)
  • Cited by (0)

    View full text