Platelets in Alcohol-Associated Liver Disease: Interaction With Neutrophils

Abstract

Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet-neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet-neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.

Keywords: Alcoholic Liver Disease; Immunity; Inflammation; Neutrophils; Platelets.

Figure 1

Mechanisms and effects of platelet–neutrophil interaction in ALD. In the presence of alcohol, platelets and neutrophils in the liver undergo activation. Platelet activation exposes p-selectin, initiating interactions between ligands and receptors, including the P-selectin–PSGL-1 interaction, leading to the formation of platelet–neutrophil complexes. As platelet granule content increases, the release of substances such as oxygen species (ROS), myeloperoxidase (MPO), and neutrophil elastase (NE) further intensifies neutrophil activation. The coordinated activation of platelets and neutrophils through pathways such as HMGB1 and TLR4 ultimately triggers the release of DNA traps by neutrophils, a process known as NETosis. NETs harbor proteinases such as cathepsin G, NE, and MPO, all capable of activating platelets and provoking inflammatory immune responses. Multiple positive feedback loops operate at various levels within this system, implicating both platelets and neutrophils in ALD. CCL5, C-C motif ligand 5; CX3CR1, C-X-C chemokine receptor 1; G-CSF, granulocyte colony-stimulating factor; JAM-3, junctional adhesion molecule 3; LFA-1, lymphocyte function-associated antigen-1; LL37, cathelicidin peptide; Mac-1, macrophage-1 antigen; P2Y12, purinergic receptor; TF, tissue factor; TREM-1, triggering receptor expressed on myeloid cells-1; TREM-1L, TREM-1 ligand. The illustration was created with BioRender.com.

Figure 2

Therapeutic approaches of targeting platelet–neutrophil in ALD. (A) Targeting neutrophil infiltration. Inhibition of proinflammatory mediators of neutrophils is a potential strategy for targeted neutrophilic therapy, including inhibition of MPO (PF-1355) and regulation of matrix metalloproteinases (MMPs) (doxycycline). Targeting neutrophil tubulin (colchicine) and antagonistic CCD18/CD11 integrin receptors on neutrophils inhibit neutrophilic recruitment to reduce inflammatory responses. (B) Targeting platelet–neutrophil interaction. This direction mainly is through targeting NETs, including DNase I, sivelestat, and taurine chloramine used to decompose NETs, molecular regulators that inhibit NET formation (peptidyl arginine deiminase 4 [PAD4]), colchicine, anticitrullinated protein antibody (tACPA), aspirin, and Mesenchymal stromal cell (MSC)-derived apoptotic vesicles (apoVs). There also are some anti-inflammatory mediators such as antigen-presenting cells (APCs), CTLR2, TLR4, TLR9 antagonists, C-X-C chemokine receptor (CXCR)1/2 blockers, and so forth. Additionally, nanoparticles modified with α1-antitrypsin are anchored to NPAs. The illustration was created with BioRender.com.