Many people who die from sepsis die of organ failure, including liver failure, which is a common, often fatal complication. For many years, the underlying causes and mechanisms of sepsis-induced liver damage remained a medical mystery.

Ping Wang, MD, and Monowar Aziz, PhD, of the Feinstein Institutes for Medical Research in Manhasset, New York, have attempted to shed light on that process, publishing new findings based on their observations on cecal ligation and puncture (CLP)-induced sepsis in mice.

Neutrophils are our most abundant type of white blood cell and the first to respond against infections. They eject protein-arginine deiminase type-4, forming neutrophil extracellular traps (NETs) to trap and kill pathogens. These NETs, however, contain several inflammatory molecules, making excessive NETs dangerous.

“Our discovery first revealed that upon inflammation, neutrophils release their intracellular DNA content, forming neutrophil extracellular traps (NETs). These NETs, decorated with toxic molecules, profoundly activate liver-resident macrophages (Kupffer cells) to release inflammatory mediators, ultimately leading to liver cell death,” said Wang. 

The Portal Vein as Pathway

Kupffer cells live in the lumen of our liver sinusoids — the main site of blood flow and material exchange in the liver — to prevent bacteria, bacterial endotoxins, and microbial debris from our gastrointestinal system from entering via the portal vein. Endogenous inflammatory molecules from the NETs trigger an aberrant activation of Kupffer cells by stimulating a receptor called protease-activated receptor-1. This activation then results in the release of proinflammatory mediators, such as cytokines, which injure surrounding hepatocytes.

Because the portal vein connects the gut and liver, Wang and his team hypothesized that this liver injury, driven by Kupffer cells and proinflammatory mediators, was simultaneously driven by the gut — specifically caused and exacerbated by proinflammatory gut intraepithelial lymphocytes and their proinflammatory interactions with neutrophils. These interactions through the protein CD112 are what train our neutrophils to subsequently cause more damage.

“Indeed, we subsequently discovered that this NET-forming, deleterious subset of neutrophils is generated in the inflamed gut through interaction with gut-specific lymphocytes,” Wang said. “This devastating neutrophil subset then migrates from the gut, homes to the liver, and causes irreversible damage to the liver, ultimately leading to death.”

By identifying this phenomenon of cellular crosstalk between the gut and liver, Feinstein researchers were able to uncover a key relationship between organs during sepsis. Examining the intricacies of this relationship has the potential to reshape our fundamental understanding of sepsis pathology, particularly where sepsis-induced damage starts and how it can spread. 

“Organ-to-organ crosstalk refers to the bidirectional communication and interaction between distinct organs, essential for coordinating systemic functions and maintaining overall homeostasis,” said Wang. “Normally, gut-liver crosstalk is a crucial symbiotic relationship. The gut delivers absorbed nutrients, metabolites, and some microbial products to the liver via the portal vein for processing and detoxification. In return, the liver supplies bile acids vital for gut digestion. This intricate interaction maintains metabolic and immune balance throughout the body.”

“In sepsis, however, this beneficial crosstalk becomes highly dysregulated and pathogenic,” he continued. “Compromise of the gut barrier (leaky gut) leads to the translocation of bacteria and potent inflammatory mediators directly to the liver via the portal circulation. This overwhelms the liver’s processing capacity, triggering exacerbated inflammation, activating Kupffer cells, causing profound metabolic dysfunction, and severe liver injury. This vicious cycle significantly worsens systemic sepsis and contributes to multi-organ failure.”

How This May Lead to Sepsis Therapies

“When I began to study sepsis approximately 40 years ago, relatively little was known about the molecular and cellular physiology of sepsis,” said W. Conrad Liles, MD, PhD, founding director of the Sepsis Center of Research Excellence-University of Washington, Seattle.

He points to seminal research advances in the role of innate immunity in sepsis: 

• The discovery of pathogen-associated molecular patterns and their interaction with pathogen recognition receptors
• Recognition that sepsis is more than “rogue inflammation,” with endothelial activation/dysfunction playing a mechanistic role in causing end-organ injury
• Identification of a state of “immunoparalysis” that can occur in late sepsis, predisposing affected individuals to secondary infections
• Increased understanding of sepsis as a heterogeneous disorder in which affected individuals can be classified into distinct biological/molecular sub-phenotypes that may respond differently to therapeutic interventions
• Macrophages play a central role in the pathophysiology of sepsis
• Sepsis can be caused by a diverse variety of microbiological pathogens, not just bacteria

Despite all that, Liles says, no agent or drug exists to prevent and treat sepsis-induced organ failure. Current treatment is mostly limited to supportive care.

“We desperately need effective, pathogen-agnostic therapeutic agents for the treatment of sepsis that target the deleterious host responses that mediate sepsis-related complications, such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), shock caused by diffuse microvascular leakage, sepsis encephalopathy, and sepsis hepatopathy (sepsis-related liver injury),” said Liles, who was not involved in this research.

Liles, for his money, would like to see how these new findings would play out beyond animal studies. “Findings from mouse models of sepsis do not necessarily translate to clinical sepsis in humans,” he said. “Another point: Do other models of sepsis, other than CLP, show a similar prominent role for NETs/NETosis in the pathogenesis of end-organ injury? In other words, are the findings reported in this study unique to CLP, or are they generalizable across preclinical models of sepsis?”

Wang and his team are already using their findings to develop a treatment to prevent liver damage.

“Inhibiting the trafficking of [the] devastating neutrophil subset from the gut to the liver by blocking portal vein blood flow is unrealistic,” said Wang. “Instead, we have identified a new therapeutic target: preventing the generation of these gut-primed, NET-forming neutrophils by disrupting the interaction between gut-resident lymphocytes and neutrophils through their specific receptors.”

“Indeed, our ongoing work has led to the discovery and development of a novel small peptide that inhibits this interaction in the gut, thereby completely preventing the generation of these gut-primed, NET-forming neutrophils,” he continued. “We have successfully treated septic animals with this peptide, inhibiting liver injury by mitigating the detrimental impact of gut-liver crosstalk mediated by this gut-derived neutrophil subpopulation. We are now rigorously verifying our data and preparing to publish a new paper on the impact of therapeutically targeting this novel mechanism to mitigate liver injury in sepsis.”

The study authors reported no financial conflicts.