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Kupffer cell-derived TNF-? promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells.

ABSTRACT: The damage-associated molecular pattern molecules (DAMPs) released by necrotic cells can trigger inflammatory response, which will facilitate the clearance of these dead cells. Neutrophil mobilization is a very important step for the dead cell clearance, however the detailed mechanisms for DAMPs induce neutrophil mobilization remains largely elusive. In this study, by using a necrotic cell-induced neutrophil mobilization mice model, we found that both neutrophil number and percentage rapidly (as early as 30 min) increased with necrotic cells but not live cell treatment. CXCL1 was rapidly increased in the serum and was responsible for the neutrophil mobilization when treated with necrotic cells. We further demonstrated that the hepatocytes in the liver were the main source of CXCL1 production in response to necrotic cells challenge. However, the hepatocytes did not express CXCL1 when incubating with necrotic cells alone. When Kupffer cells were ablated, the increased CXCL1 levels as well as neutrophil mobilization were abolished with necrotic cells challenge. Moreover, we clarified Kupffer cells-derived TNF-? activates the NF-?B pathway in hepatocytes and promote hepatocytes to express CXCL1. In summary, we showed that the liver is the main source for necrotic cell-induced CXCL1 production and neutrophil mobilization. Kupffer cells in the liver sense DAMPs and release TNF-? to activate the NF-?B pathway in hepatocytes. The interaction between Kupffer cells and hepatocytes is critical for CXCL1 production.

SUBMITTER: Su L

PROVIDER: S-EPMC5833701 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells.

Su Li L Li Na N Tang Hua H Lou Ziyang Z Chong Xiaodan X Zhang Chenxi C Su Jiacan J Dong Xin X

Cell death & disease 20180223 3

The damage-associated molecular pattern molecules (DAMPs) released by necrotic cells can trigger inflammatory response, which will facilitate the clearance of these dead cells. Neutrophil mobilization is a very important step for the dead cell clearance, however the detailed mechanisms for DAMPs induce neutrophil mobilization remains largely elusive. In this study, by using a necrotic cell-induced neutrophil mobilization mice model, we found that both neutrophil number and percentage rapidly (as ...[more]

PMID: 29476069

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Project description:Polymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human-pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and the release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. To assess as a proof of concept whether the antimicrobial proteins found in afEVs might contribute to growth inhibition of hyphae when present in the fungal cytoplasm, two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae. This led to reduced fungal growth relative to that of a control strain producing the human retinol binding protein 7. In conclusion, extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. This finding offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus IMPORTANCE Invasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high rates of mortality, as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We found that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.

Dataset Information

Kupffer cell-derived TNF-? promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells.

Publications

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells.

Similar Datasets

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