The Effects of Pathogen-Associated Molecular Patterns on Peripheral Blood Monocytes in Patients with Non-alcoholic Fatty Liver Disease

Qian Li; Julia D Rempel; Jiaqi Yang; Gerald Y Minuk

doi:10.1016/j.jceh.2021.11.011

The Effects of Pathogen-Associated Molecular Patterns on Peripheral Blood Monocytes in Patients with Non-alcoholic Fatty Liver Disease

J Clin Exp Hepatol. 2022 May-Jun;12(3):808-817. doi: 10.1016/j.jceh.2021.11.011. Epub 2021 Nov 25.

Authors

Qian Li^{1

2}, Julia D Rempel^{1

2}, Jiaqi Yang¹, Gerald Y Minuk^{1

3}

Affiliations

¹ Section of Hepatology, University of Manitoba, Winnipeg, Manitoba, Canada.
² Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
³ Departments of Medicine, Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.

Abstract

Background: Innate immune responses to gut-derived pathogen-associated molecular patterns (PAMPs) have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether NAFLD patients have increased sensitivity to PAMP exposure has yet to be reported.

Methods: Peripheral blood mononuclear cell (PBMC)/monocytes were exposed to lipopolysaccharide (LPS), Pam3CSK4, or BSA conjugated palmitate in vitro. Changes in toll-like receptors (TLR), cytokines, and chemokine receptors (CR) expressions were documented by flow cytometry and/or enzyme-linked immunoabsorbent assays (ELISAs).

Results: TLR2 and TLR4 expression were similar at baseline and increased to a similar extent (TLR2) or remained unchanged (TLR4) following PAMP exposure in NAFLD and healthy control (HC) monocytes. Proinflammatory IL-1β and IL-6 levels were similar at baseline but increased in a concentration-dependent manner to a greater extent in NAFLD PBMCs. CCR1 and CCR2 expressions at baseline were similar and decreased to a similar extent in NAFLD and HC monocytes. The extent of PAMP-induced proinflammatory cytokine release correlated with evidence of hepatocyte injury (CK18M30 levels).

Discussion: NAFLD patients have increased proinflammatory cytokine responses following exposure to PAMPs relative to HC subjects. This response is concentration-dependent and correlates with the extent of hepatic injury.

Keywords: ALT, alanine aminotransferase; CM, culture medium; CR, chemokine receptor; ELISAs, enzyme-linked immunoabsorbent assays; HC, healthy controls; LPS, lipopolysaccharide; NAFLD; NAFLD, nonalcoholic fatty liver disease; NASH; PAMPs; PAMPs, pathogen-associated molecular patterns; PBMC, peripheral blood mononuclear cell; Pal, palmitate; Pam, Pam3CSK4; TLR, toll-like receptor; nonalcoholic fatty liver disease; pathogen-associated molecular patterns.