Necroptosis contributes to chronic inflammation and fibrosis in aging liver

Sabira Mohammed; Nidheesh Thadathil; Ramasamy Selvarani; Evan H. Nicklas; Dawei Wang; Benjamin F. Miller; Arlan Richardson; Sathyaseelan S. Deepa

doi:10.1111/acel.13512

journal article Open Access Nov 11, 2021

Necroptosis contributes to chronic inflammation and fibrosis in aging liver

Sabira Mohammed

Nidheesh Thadathil

Ramasamy Selvarani Evan H. Nicklas Dawei Wang

Benjamin F. Miller

Arlan Richardson

Sathyaseelan S. Deepa

Aging Cell Vol. 20 No. 12 · Wiley

View at Publisher Save 10.1111/acel.13512

Abstract

Abstract
Inflammaging, characterized by an increase in low‐grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age‐related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age‐associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of pro‐inflammatory cytokines (TNFα, IL6 and IL1β), and markers of fibrosis were all significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of pro‐inflammatory cytokines relative to young mice. Short‐term treatment with the necroptosis inhibitor, necrostatin‐1s (Nec‐1s), reduced necroptosis, markers of M1 macrophages, fibrosis, and cell senescence as well as reducing the expression of pro‐inflammatory cytokines in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD.

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Details

Published: Nov 11, 2021
Vol/Issue: 20(12)
License: View

Authors

S

Sabira Mohammed

Stephenson Cancer Center Oklahoma City OK USA

N

Nidheesh Thadathil

Department of Biochemistry and Molecular Biology Oklahoma City OK USA

R

Ramasamy Selvarani

Department of Biochemistry and Molecular Biology Oklahoma City OK USA

E

Evan H. Nicklas

Department of Biochemistry and Molecular Biology Oklahoma City OK USA

D

Dawei Wang

Department of Biochemistry and Molecular Biology Oklahoma City OK USA

B

Benjamin F. Miller

Department of Biochemistry and Molecular Biology Oklahoma City OK USA; Oklahoma Center for Geroscience & Brain Aging University of Oklahoma Health Sciences Center Oklahoma City OK USA; Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City OK USA

A

Arlan Richardson

Stephenson Cancer Center Oklahoma City OK USA; Department of Biochemistry and Molecular Biology Oklahoma City OK USA; Oklahoma Center for Geroscience & Brain Aging University of Oklahoma Health Sciences Center Oklahoma City OK USA; Oklahoma City VA medical Center Oklahoma City OK USA

S

Sathyaseelan S. Deepa

Stephenson Cancer Center Oklahoma City OK USA; Department of Biochemistry and Molecular Biology Oklahoma City OK USA; Oklahoma Center for Geroscience & Brain Aging University of Oklahoma Health Sciences Center Oklahoma City OK USA

Funding

National Institutes of Health Award: R01AG059718

Cite This Article

Sabira Mohammed, Nidheesh Thadathil, Ramasamy Selvarani, et al. (2021). Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell, 20(12). https://doi.org/10.1111/acel.13512

Necroptosis contributes to chronic inflammation and fibrosis in aging liver

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