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

Chhagan Bihari; Sukriti Baweja; Seggere Murlaikrishna Shasthry; Deepika Lal; Preeti Negi; Swati Thangariyal; Dinesh Mani Tripathi; Shiv Kumar Sarin

doi:10.14218/JCTH.2021.00331

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

J Clin Transl Hepatol. 2022 Feb 28;10(1):53-62. doi: 10.14218/JCTH.2021.00331. Epub 2022 Jan 4.

Authors

Chhagan Bihari¹, Sukriti Baweja², Seggere Murlaikrishna Shasthry³, Deepika Lal², Preeti Negi², Swati Thangariyal², Dinesh Mani Tripathi², Shiv Kumar Sarin^{2

3}

Affiliations

¹ Department of Pathology and Hematology, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi, India.
² Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi, India.
³ Department of Hepatology, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi, India.

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.

Keywords: Bone marrow; CEACAM-1; CSF3R; Child-Turcott-Pugh score; Granulocyte colony stimulating factor; Hematopoietic stem cells; Liver cirrhosis; Neutropenia.