Fibrocytes in Chronic Periaortitis: A Novel Mechanism Linking Inflammation and Fibrosis

Abstract

Objective Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. Methods We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti–type I procollagen, anti‐CXCR4, and anti‐CD45 antibodies and analyzed by confocal microscopy to detect tissue‐infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme‐linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. Results The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls (P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls (P = 0.0056), and tissue‐infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin‐13 [IL‐13] and IL‐10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA‐3+ cells, also indicating Th2 polarization; Th2‐skewed responses are known to promote fibrocyte differentiation. Conclusion Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2‐skewed immune responses are likely to facilitate their differentiation.

Immune Dysregulation in IgG4-Related Disease

“…Another study, however, examined 44 patients with chronic periaortitis, one of the subtypes of IgG4-RD, and demonstrated the elevated level of CXCL12 and dominant infiltration of GATA3 + Th2 cells. This novel finding indicates CXCL12 might drive fibrocytes accumulation and Th2 differentiation ( 40 ).…”

Case Report: A Programmed Cell Death-1 Inhibitor-Related Abdominal Fibroinflammatory Reaction Affecting Multiple Organs in A Non-Small-Cell Lung Cancer Patient

“…The IgG4 subclass of antibodies is expressed in alternative Th2 environments characterized by high levels of IL-10 ( 21 ). Furthermore, when an enhanced Th2 signal is observed, cytokines related to Th2 signaling, such as IL-10 and IL-13 are found to be elevated ( 22 ). It is known that Th2-skewed responses favor fibrocyte differentiation.…”

CXCL12/SDF-1 in IgG4-Related Disease

“…In a mouse model of lung fibrosis, it has been shown that human fibrocytes migrate in response to SDF-1/CXCL12 and localize to lungs if injected in bleomycin-treated animals ( Phillips et al, 2004 ). An increase in the number of collagen-positive fibrocytes was detected in chronic periaortitis patients, both in peripheral blood and in the affected tissue ( Nicastro et al, 2019 ). Similarly, in IgG4-RD patients, SDF-1/CXCL12 may recruit fibrocytes to affected organs, driving tissue fibrosis.…”

“…Recent data draw attention to the role of SDF-1/CXCL12 as a mediator involved in recruiting circulating fibrocytes to the inflamed tissue in chronic periaortitis, a fibrotic disorder in the spectrum of IgG4-RD ( Nicastro et al, 2019 ).…”