CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Abstract

Background and Aims Cirrhosis patients exhibit cytopenia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We conducted this study to assess the CSF3R status and its relevance in cirrhotic patients. Methods Cirrhotic patients ( n =127) and controls ( n =26) with clinically indicated bone marrow (BM) examination were studied. BM assessment was done by qRT-PCR and immunohistochemistry (IHC) for CSF3R . Circulating G-CSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated in liver cirrhosis patients who received G-CSF for severe neutropenia. Results The mean age was 48.6±13.4 years, and 80.3% were men. Circulatory CSF3R reduction was noted with the advancement of cirrhosis, and confirmed by qRT-PCR and IHC in BM. CSF3R decline was related to decreased hematopoietic stem cells (HSCs) and downregulation of CSF3R in the remaining HSCs. Cocultures confirmed that CEACAM1 led to CSF3R downregulation in BM cells by possible lysosomal degradation. Baseline low peripheral blood-(PB)-CSF3R also predisposed development of infections on follow-up. Decreased CSF3R was also associated with nonresponse to exogenous G-CSF treatment of neutropenia. Conclusions Advanced liver cirrhosis was associated with low CSF3R and high CEACAM1 levels in the BM and circulation, making patients prone to infection and inadequate response to exogenous G-CSF.

Progressive dysfunction of the immune system as a factor preventing recoverable regeneration of the liver in chronic fibrosing diseases

“…Следствием развития этих нарушений в костном мозге становится устойчивая и тяжёлая дисрегуляция (торможение) процессов восстановительной регенерации клеток крови и иммунных клеток в центральном и периферических органах иммуногенеза (костный мозг, селезёнка и лимфоузлы), что проявляется цитопенией в периферической крови, гиперспленией и прогрессированием фиброза и цирроза печени [95]. Снижение регенераторного потенциала гемопоэтических и мезенхимальных стволовых/ прогениторных клеток костного мозгa при циррозе печени является также фактором ограниченной (слабо выраженной) эффективности активационного терапевтического воздействия на клетки костного мозгa больного эндогенных и экзогенных факторов роста [96,97], а также аутологичных клеток костного мозгa при их трансплантации [98]. При прогрессирующем циррозе печени терапия аутологичными или аллогенными клетками костного мозгa [(гемопоэтические стволовые/прогениторные клетки или мезенхимальные/стромальные клетки (МСК)] от здорового донора не всегда оказывалась эффективной и даже была способна усилить эффект повреждения и фиброзирования печени [99], что, возможно, обусловлено более интенсивной активацией дифференцировки отдельных субпопуляций МСК в миофибробласты в профибротическом микроокружении [100].…”

Sending an SOS: Healing the Liver with the Bone Marrow

“…In a study published in this issue, Bihari et al . 10 assessed the CSF3R status in cirrhotic patients and showed that they have lower levels of CSF3R but higher levels of CEACAM1. The authors performed bone marrow examination in 127 cirrhotic patients and 26 controls and profiled cirrhosis patients by measuring G-CSF, CSF3R, and CEACAM1 in the bone marrow and peripheral blood by qRT-PCR and immunohistochemistry.…”

“…It has been proposed that restoring bone marrow function may provide new therapeutic options for patients with cirrhosis. 10 As CEACAM-1 downregulates CSF3R and is positively correlated with G-CSF, inhibiting it may be a viable treatment option. That is important, as elevated G-CSF can induce hematopoietic stem cells to enter into refractory colony formation stages, which can further decrease bone marrow function.…”

“…In summary, Bihari et al . 10 have shed light on the molecular mechanisms that lead to bone marrow dysfunction in patients with cirrhosis, and to an unexplored avenue of treatment that may impact patient survival. Further exploration of the relationship between G-CSF, its receptor CSF3R, and CEACAM-1 is warranted.…”