Diminished non-classical monocytes in the blood associate with disease severity in alcoholic hepatitis

TY - JOUR

T1 - Diminished non-classical monocytes in the blood associate with disease severity in alcoholic hepatitis

AU - Rasmussen, Elisabeth Busk

AU - Eriksen, Lotte Lindgreen

AU - Greisen, Stinne Ravn

AU - Hansen, Anne Louise

AU - Carstensen, Mikkel

AU - Sandahl, Thomas Damgaard

AU - Støy, Sidsel

AU - Kragstrup, Tue Wenzel

N1 - Funding Information: TWK was supported by a grant from Independent Research Fund Denmark (9039-00015B). Publisher Copyright: © 2021 Rasmussen et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - Objective: Alcoholic hepatitis (AH) holds a high mortality, and vast macrophage infiltration of the liver is involved in the progressive liver injury. No efficient medical treatment exists, and macrophages may be a future treatment target. Here, we examine associations between non-classical monocyte subsets and cell surface markers of migration with disease activity in patients with severe AH. Methods: We analyzed samples from two cohorts of patients with AH. Cohort 1 included 15 AH patients, followed for 30 days, and 8 healthy controls (HCs). Cohort 2 included 23 AH patients, followed for 90 days, and 9 HCs. Peripheral blood mononuclear cells (PBMCs) from both cohorts were analyzed by flow cytometry. Liver biopsies from cohort 2 were analyzed by RNA sequencing. Results: Circulating non-classical monocytes in all but absent in patients with AH compared to HC in both cohorts (both p<0.0001). The frequency of non-classical monocytes was significantly associated with Maddrey’s discriminant function (mDF) (r=−0.79, p=0.0008, cohort 1), Child–Pugh score (CP) (r=−0.56, p=0.03, cohort 1), Model for End-Stage Liver Disease (MELD) (r=−0.54, p=0.02, cohort 2) and C-reactive protein (CRP) (r=−0.51, p=0.027, cohort 2). The surface expression of CD11b was increased on non-classical mono-cytes in patients with AH compared to HC (p<0.0001) (cohort 1). The mRNA expression of CD11b was increased in liver biopsies in patients with AH compared to HC (cohort 2) (p<0.0001). Conclusion: In this study, we describe an almost complete depletion of circulating non-classical monocytes in the blood in two independent cohorts of patients with AH, which may be associated with a possible harmful recruitment of these cells to the liver. These results contribute to a better understanding of the disease, which hopefully can lead to therapies that target the acute inflammatory response leading to severe AH.

AB - Objective: Alcoholic hepatitis (AH) holds a high mortality, and vast macrophage infiltration of the liver is involved in the progressive liver injury. No efficient medical treatment exists, and macrophages may be a future treatment target. Here, we examine associations between non-classical monocyte subsets and cell surface markers of migration with disease activity in patients with severe AH. Methods: We analyzed samples from two cohorts of patients with AH. Cohort 1 included 15 AH patients, followed for 30 days, and 8 healthy controls (HCs). Cohort 2 included 23 AH patients, followed for 90 days, and 9 HCs. Peripheral blood mononuclear cells (PBMCs) from both cohorts were analyzed by flow cytometry. Liver biopsies from cohort 2 were analyzed by RNA sequencing. Results: Circulating non-classical monocytes in all but absent in patients with AH compared to HC in both cohorts (both p<0.0001). The frequency of non-classical monocytes was significantly associated with Maddrey’s discriminant function (mDF) (r=−0.79, p=0.0008, cohort 1), Child–Pugh score (CP) (r=−0.56, p=0.03, cohort 1), Model for End-Stage Liver Disease (MELD) (r=−0.54, p=0.02, cohort 2) and C-reactive protein (CRP) (r=−0.51, p=0.027, cohort 2). The surface expression of CD11b was increased on non-classical mono-cytes in patients with AH compared to HC (p<0.0001) (cohort 1). The mRNA expression of CD11b was increased in liver biopsies in patients with AH compared to HC (cohort 2) (p<0.0001). Conclusion: In this study, we describe an almost complete depletion of circulating non-classical monocytes in the blood in two independent cohorts of patients with AH, which may be associated with a possible harmful recruitment of these cells to the liver. These results contribute to a better understanding of the disease, which hopefully can lead to therapies that target the acute inflammatory response leading to severe AH.

KW - Alcoholic hepatitis

KW - CCR2

KW - CD11b

KW - CX3CR1

KW - Monocytes

KW - Non-classical

UR - http://www.scopus.com/inward/record.url?scp=85108429420&partnerID=8YFLogxK

U2 - 10.2147/CEG.S299775

DO - 10.2147/CEG.S299775

M3 - Journal article

C2 - 34135614

AN - SCOPUS:85108429420

SN - 1178-7023

VL - 14

SP - 259

EP - 267

JO - Clinical and Experimental Gastroenterology

JF - Clinical and Experimental Gastroenterology

ER -