Can you write reference papers ( highly cited, high impact journals from last 5 years) supporting the points mentioned in the review article points written here in the text  Role of LSECs in Modulating the Immune Response: Antigen Presentation and Immune Tolerance
Liver Sinusoidal Endothelial Cells (LSECs) are central to the liver's ability to regulate immune responses, primarily through their unique capacity for antigen presentation. Unlike traditional antigen-presenting cells (APCs) such as dendritic cells, LSECs function as non-professional APCs. They capture antigens from the bloodstream through scavenger receptors and present them to T cells in a manner that generally promotes immune tolerance. This process is crucial because the liver is constantly exposed to antigens from the gut, including food antigens, microbial products, and toxins. If the liver were to react aggressively to every antigen, it could lead to chronic inflammation and damage. LSECs help prevent this by promoting a state of tolerance through their presentation of antigens to T cells in a manner that induces T cell inactivation or regulatory T cell (Treg) differentiation, rather than T cell activation. This function of LSECs is fundamental to the liver’s ability to tolerate harmless antigens and maintain immune homeostasis, protecting the liver from immune-mediated injury.
Communication of LSECs with Immune Cells: T Cells, Macrophages, and Kupffer Cells
LSECs actively communicate with a variety of immune cells within the liver, including T cells, macrophages, and Kupffer cells, to modulate immune responses and prevent excessive activation. One of their most critical interactions is with T cells, particularly through antigen presentation. LSECs present antigens via major histocompatibility complex (MHC) class I and II molecules, but instead of activating these T cells, they often induce a state of tolerance. Through this interaction, LSECs can inhibit effector T cell proliferation and promote the differentiation of regulatory T cells (Tregs), which play a key role in suppressing immune responses and preventing autoimmune reactions.
In addition to T cells, LSECs interact closely with Kupffer cells, the liver's resident macrophages, which are crucial for maintaining immune surveillance. Kupffer cells are responsible for removing pathogens, cellular debris, and other foreign particles from the blood. LSECs, by continuously filtering the blood and presenting antigens, provide signals to Kupffer cells about the nature of antigens in the bloodstream. This interaction helps Kupffer cells determine whether to initiate an immune response or maintain tolerance. Together, LSECs and Kupffer cells form a crucial regulatory network that ensures the liver responds appropriately to potential threats while preventing overactivation of the immune system.

LSECs also interact with circulating macrophages and monocytes that enter the liver. LSECs release soluble factors, such as interleukins (e.g., IL-10), which can have anti-inflammatory effects, and these signals influence macrophages toward a more regulatory or tolerogenic phenotype. This collaboration ensures that the liver remains an immune-privileged organ, capable of responding to pathogens without causing unnecessary inflammation or fibrosis.
Dysregulation of LSEC Functions and Contribution to Inflammatory Liver Diseases
Recent research has highlighted that when LSECs become dysfunctional, they can contribute significantly to the pathogenesis of various inflammatory liver diseases. In chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, the immune-regulatory capacity of LSECs is often compromised. One of the key changes observed in dysfunctional LSECs is the loss of their fenestrations, a process known as capillarization, which makes them more like conventional vascular endothelial cells. This structural change disrupts their ability to filter antigens and modulate immune responses effectively.
Dysfunctional LSECs may also lose their ability to induce tolerance in T cells, leading to excessive T cell activation and chronic inflammation. Instead of promoting immune suppression, LSECs can present antigens in a pro-inflammatory context, contributing to the activation of T cells and the recruitment of other immune cells, such as neutrophils and macrophages, into the liver. This immune overactivation exacerbates liver injury, promoting further hepatocyte damage and fibrosis. Additionally, in conditions such as cirrhosis, LSECs are involved in the progression of fibrosis by altering their communication with hepatic stellate cells (HSCs). Normally, LSECs release factors that keep HSCs in a quiescent state. However, under inflammatory conditions, dysfunctional LSECs can release pro-fibro genic signals, contributing to the activation of HSCs, which leads to increased collagen production and fibrosis.
Studies have also shown that oxidative stress, driven by conditions like fatty liver disease or alcohol-induced liver injury, can impair LSEC function. When oxidative stress increases, LSECs release inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), contributing to the inflammatory milieu in the liver. Over time, these changes promote the progression from simple inflammation to chronic liver diseases such as cirrhosis and hepatocellular carcinoma (HCC).
LSECs are essential for maintaining immune tolerance and preventing liver inflammation, their dysregulation can have profound effects, leading to immune activation, chronic inflammation, and fibrosis in liver disease. Continued research into the mechanisms of LSEC dysfunction offers promising avenues for developing targeted therapies to restore LSEC function and halt the progression of liver disease.