Circulating fibrocytes are involved in inflammation and leukocyte trafficking in neonates with necrotizing enterocolitis

Abstract

Fibrocytes, ahematopoietic stem cell source of fibroblasts/myofibroblasts, were previously implicated to infiltrate into the intestinal and enhance inflammation.The aims of the present study were to elucidate the role of fibrocytes in necrotizing enterocolitis (NEC) pathogenesis and to explore the mechanisms by which fibrocytes contributed to the inflammatory responses.We investigated circulating and intestinal local fibrocytes from 32 patients with NEC, 8 patients with noninflammatory conditions of the gastrointestinal tract and 12 normal subjects.Significantly higher numbers of circulating fibrocytes were found in the peripheral blood from NEC patients than the controls (P < .01). Numerous fibrocytes were found infiltrating the NEC intestinal mucous membranes. The percentage of fibrocytes to total leukocytes in the NEC inflammatory lesions was significantly increased compared with the percentage in the noninflammatory gastrointestinal tract. The fibrocyte attractant chemokine C-X-C motif chemokine ligand 12 (CXCL12) was significantly increased in the plasma and was detectable in 80% of the peritoneal lavage fluid from NEC patients but not the controls. Furthermore, chemokine expression was increased in fibrocytes infiltrating and trafficking to leukocyte sites. In culture, lipopolysaccharide (LPS) induced a significant increase in the expression of the Toll-like receptor (TLR4) signal, with the upregulation of p38 in both the isolated fibrocytes and macrophages. Similarly, interleukin (IL)-1β induced increased the upregulation of the IL-6, tumor necrosis factor (TNF)-α, and intercellular cell adhesion molecule-1 mRNAs but downregulated ColI in fibrocytes isolated from NEC patients compared with the controls.These findings indicate that circulating fibrocytes are increased in NEC patients and may be recruited to the inflammatory intestinal track, most likely through the CXCR4/CXCL12 axis. These cells may contribute to intestinal inflammation through TLR4 signaling by producing the TNF-α and IL-6 cytokines.

Fibrocytes, Wound Healing, and Corneal Fibrosis

“…59 Fibrocytes were recently implicated in the inflammation associated with necrotizing enterocolitis in neonates and are most likely recruited to the intestine through the CXCR4/CXCL12 axis. 60 CCR2 is a receptor for the chemokine (C-C motif) ligand 2 (CCL2), which is also called monocyte chemoattractant protein-1. 25 Reich et al 14 investigate the role of CCR2 in the migration of fibrocytes in a murine model of obstructed kidney using CCR2-null mice.…”

“…40 They are unique cells that exhibit the proinflammatory properties of macrophages and the tissue remodeling properties of fibroblasts. Fibrocytes contribute to wound healing by numerous mechanisms: (I) by acting as antigen-presenting cells capable of stimulating 35,40,60,[74][75][76] CCL2, CC-chemokine ligand 2, also known as monocyte chemoattractant protein-1; CCL3, CC-chemokine ligand 3, also known as macrophage inflammatory protein 1-α; CCL4, CC-chemokine ligand 4, also known as macrophage inflammatory protein 1-β; CXCL1, CXC-chemokine ligand 1, also known as GRO alpha; CXCL2, CXC-chemokine ligand 2, also known as macrophage inflammatory protein 2; CXCL8, CXCchemokine ligand 8, also known as IL-8; CTGF, connective tissue growth factor; M-CSF, macrophage colony-stimulating factor; IGF-1, insulin-like growth factor-1; FGF2, fibroblast growth factor 2; VEGF, vascular endothelial growth factor. T-cell-mediated immunity 40 ; (II) by directly depleting pathogens through the release of extracellular traps, lysosomal peptides, 65 as well as by recently demonstrated phagocytic activity 66 ; (III) by producing cytokines, chemokines, and growth factors important for wound repair (see Table 3) 35,67,68 ; (IV) by secreting extracellular matrix proteins and glycosaminoglycans (see Table 1); (V) by promoting wound closure via α-SMA-mediated contraction 27 ; (VI) by promoting angiogenesis, 67,68 via secretion of growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 and vascular endothelial growth factor; and (VII) by transforming into other mesenchymal cell types, in addition to fibroblasts and myofibroblasts, such as adipocytes, that contribute to new-tissue formation.…”

Inhibitory effect of circulating fibrocytes on injury repair in acute lung injury/acute respiratory distress syndrome mice model

“…Therefore, CFs have been found to be associated with several inflammatory and fibrotic diseases. For instance, CFs number was increased in inflammatory bowel disease and necrotizing enterocolitis to recruit fibrocytes in injured sites and promoted inflammation. They were also proved to be involved in inflammation and fibrosis progression of lung as increased numbers of fibrocytes in bronchopulmonary dysplasia patients contributed to pulmonary fibrosis .…”

Detection of bone marrow‐derived fibrocytes in human dental pulp repair

“…Fibrocytes—distinguished from peripheral blood leucocytes by CD45 and collagen I co‐expression—can infiltrate into sites of injury (Liu et al . ). Therefore, in this study, CD45+/pro‐collagen I+ co‐expression was used to identify fibrocytes.…”

“…In addition, CD34 expression in fibrocytes decreases over time, and, therefore, the co-expression of CD45 and collagen I is frequently used to identify fibrocytes (Strieter et al 2009). Fibrocytes-distinguished from peripheral blood leucocytes by CD45 and collagen I co-expression-can infiltrate into sites of injury (Liu et al 2017). Therefore, in this study, CD45+/pro-collagen I+ co-expression was used to identify fibrocytes.…”