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Neutrophils insert elastase into hepatocytes to regulate calcium signaling in alcohol-associated hepatitis
Noriyoshi Ogino, … , Barbara E. Ehrlich, Michael H. Nathanson
Noriyoshi Ogino, … , Barbara E. Ehrlich, Michael H. Nathanson
Published June 25, 2024
Citation Information: J Clin Invest. 2024;134(16):e171691. https://doi.org/10.1172/JCI171691.
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Research Article Hepatology Article has an altmetric score of 11

Neutrophils insert elastase into hepatocytes to regulate calcium signaling in alcohol-associated hepatitis

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Abstract

Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to digest phagocytosed bacteria and foreign substances or neutralize them in neutrophil extracellular traps. In certain pathological states, granule proteases play a destructive role against the host as well. More recently, nondestructive actions of neutrophil granule proteins have been reported, such as modulation of tissue remodeling and metabolism. Here, we report a completely different mechanism by which neutrophils act nondestructively, by inserting granules directly into hepatocytes. Specifically, elastase-containing granules were transferred to hepatocytes where elastase selectively degraded intracellular calcium channels to reduce cell proliferation without cytotoxicity. In response, hepatocytes increased expression of Serpin E2 and A3, which inhibited elastase activity. Elastase insertion was seen in patient specimens of alcohol-associated hepatitis, and the relationship between elastase-mediated ITPR2 degradation and reduced cell proliferation was confirmed in mouse models. Moreover, neutrophils from patients with alcohol-associated hepatitis were more prone to degranulation and more potent in reducing calcium channel expression than neutrophils from healthy individuals. This nondestructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.

Authors

Noriyoshi Ogino, M. Fatima Leite, Mateus T. Guerra, Emma Kruglov, Hiromitsu Asashima, David A. Hafler, Takeshi Ito, João P. Pereira, Brandon J. Peiffer, Zhaoli Sun, Barbara E. Ehrlich, Michael H. Nathanson

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Figure 4

Neutrophils insert granule proteins into hepatocytes.

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Neutrophils insert granule proteins into hepatocytes.
(A) Flowchart show...
(A) Flowchart showing the protocol for fractionating neutrophils. (B) Representative immunoblots and (C) quantitation of ITPR2 in HepG2 cells after 20 hours of incubation with the indicated fractions shows that the neutrophil granule fraction is sufficient to reduce ITPR2. (D and E) Representative confocal immunofluorescence images of HepG2 cells alone (D) and after coculture with neutrophils for 1 hour, after which the cells were then washed to remove the neutrophils (E). Labels are anti-myeloperoxidase (anti-MPO, green) and anti-elastase (red) antibodies, nuclear staining (DAPI, blue), and phalloidin (gray). Scale bar: 20 μm. Inset is an ×2 enlargement showing partial colocalization of MPO and elastase (yellow). Elastase also appears to be diffusely distributed in the nucleus. (F) Representative immunoblots and (G) quantitation show the neutrophil granule proteins MPO and elastase appear in HepG2 cells after coculturing with neutrophils for 1 hour, after which the cells were washed to remove the neutrophils. All data are presented as mean ± SD; n = 4–9 (C) and n = 3 (G). NS, not significant. ****P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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