Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors

Brandel, Victoria; Schimek, Vanessa; Göber, Samantha; Hammond, Thomas; Brunnthaler, Laura; Schrottmaier, Waltraud C.; Mußbacher, Marion; Sachet, Monika; Liang, Ying; Reipert, Siegfried; Ortmayr, Gregor; Pereyra, David; Santol, Jonas; Rainer, Marlene; Walterskirchen, Natalie; Ramos, Cristiano; Gerakopoulos, Vasileios; Rainer, Carina; Spittler, Andreas; Weiss, Tamara; Kain, Renate; Meßner, Barbara; Gruenberger, Thomas; Assinger, Alice; Oehler, Rudolf; Starlinger, Patrick

doi:10.1016/j.jhep.2022.07.027

Cited by 19 publications

(28 citation statements)

References 31 publications

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“…5a-c ). A recent clinical investigation revealed that patients who underwent partial hepatectomy had a significant increase in intrahepatic neutrophils 48 . In our study, injection of C57BL/6J mice with LIFR-expressing adenovirus led to elevated levels of serum HGF after partial hepatectomy, which was reversed by neutrophil depletion with a Ly6G-specific monoclonal antibody 23 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the involvement of neutrophils in tissue injury repair has been increasingly recognized [23][24][25][26][27] . After partial hepatectomy or chemical damage (by CCl4 or acetaminophen treatment) to the liver, neutrophils accumulate at the injury site and actively participate in clearing dead cells and stimulating hepatocyte proliferation, liver tissue repair, and regeneration 23,24,48 recent study reported that genetic ablation of neutrophils in mice (by knockout of Gcsf) exacerbated tissue damage and diminished liver regeneration after injury, demonstrating the functional contribution of neutrophils to liver injury repair 23 . However, it has been unclear how the damaged liver signals to the bone marrow to release neutrophils to the bloodstream and liver, and how these neutrophils signal to hepatocytes to re-enter the cell cycle and proliferate.…”

Section: Interestingly Lifr Deficiency or Overexpression Does Not Aff...mentioning

confidence: 99%

“…In response to infection or tissue damage, neutrophils are released from the bone marrow to participate in pathogen clearance or tissue repair [45][46][47] . Interestingly, a recent study showed that in patients who had undergone surgical resection of a diseased part of the liver, a significant increase in intrahepatic neutrophils was observed during the early response to resection 48 . Consistent with this clinical observation, we found that in mice, the number of neutrophils (CD45 + CD11b + Ly6G + cells, based on flow cytometry analysis) per gram of liver increased in a time-dependent manner after partial hepatectomy and peaked at 72 hours (Fig.…”

Section: Hepatocytic Lifr Promotes Neutrophil Recruitment In Liver Re...mentioning

confidence: 99%

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LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

Deng

Zhao

Sheldon

et al. 2023

Preprint

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The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage-induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.

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Section: Resultsmentioning

confidence: 99%

Section: Interestingly Lifr Deficiency or Overexpression Does Not Aff...mentioning

confidence: 99%

Section: Hepatocytic Lifr Promotes Neutrophil Recruitment In Liver Re...mentioning

confidence: 99%

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LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

Deng

Zhao

Sheldon

et al. 2023

Preprint

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“…Such feedback-reinforced learning during infection-induced inflammation would facilitate (a) readjustment of ongoing innate and antigen-specific responses, including both gross class selection and fine modulation; and (b) beneficial participation of recruited and tissue-resident lymphocytes and non-antigen-specific effector cells in the repair and healing process. Indeed, “immune cells change rapidly and subsequently produce factors that are required for the repair of tissue damage” ( 95 ). The antigen-specific and tissue maintenance functions are coupled and simultaneous, not inherently distinct.…”

Section: Supervised Learning and Immunity: Explore With Quality Contr...mentioning

confidence: 99%

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

2023

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The systemic bio-organization of humans and other mammals is essentially “preprogrammed”, and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence – now overwhelming – suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded “algorithms” that govern the integration of signals and the computation of new states are not fully understood but are believed to be “smart”, designed to enable the cells and the system to discriminate meaningful perturbations from each other and from “noise”. Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the “training” that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.

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“…Circulating innate immune cells shall also be recruited to liver after hepatectomy and promote liver growth. Neutrophils, for instance, can be activated by apoptotic extracellular vesicles and then secrete various growth factors including fibroblast growth factor-2 and hepatocyte growth factor ( 9 ). Monocyte-derived macrophages release hepatocyte growth factor and other paracrine factors to boost liver regeneration as well, which can be influenced by endocrine and systemic inflammatory environment ( 10 , 11 ).…”

mentioning

confidence: 99%

The role of innate immune cells in post-hepatectomy liver regeneration

Huang¹,

Zhu²

2023

Hepatobiliary Surg Nutr

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Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors

Cited by 19 publications

References 31 publications

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

The role of innate immune cells in post-hepatectomy liver regeneration

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