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. 2024 Jun 25:e171691.
doi: 10.1172/JCI171691. Online ahead of print.

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

Noriyoshi Ogino  1 , M Fátima Leite  1 , Mateus T Guerra  1 , Emma Kruglov  1 , Hiromitsu Asashima  2 , David A Hafler  2 , Takeshi Ito  3 , João P Pereira  3 , Brandon J Peiffer  4 , Zhaoli Sun  4 , Barbara E Ehrlich  1 , Michael H Nathanson  1
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Free article

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

Noriyoshi Ogino et al. J Clin Invest. .
Free article

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, non-destructive 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 non-destructively, 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 subjects. This non-destructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.

Keywords: Calcium signaling; Hepatitis; Hepatology; Neutrophils.

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