The pro-apoptotic ARTS protein induces neutrophil apoptosis, efferocytosis, and macrophage reprogramming to promote resolution of inflammation

Naama Maimon, Zohar Zvi Zamir, Prajakta Kalkar, Orly Zeytuni-Timor, Sagie Schif-Zuck, Sarit Larisch, Amiram Ariel

Research output: Contribution to journalArticlepeer-review

Abstract

ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e. efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS−/− mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS−/− mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.

Original languageEnglish
Pages (from-to)558-573
Number of pages16
JournalApoptosis : an international journal on programmed cell death
Volume25
Issue number7-8
DOIs
StatePublished - 1 Aug 2020

Bibliographical note

Funding Information:
We thank Kfir Lapid, Ph.D. (Berlin, Germany) for the professional manuscript writing and editing services. The study was supported by grants from the Israel Science Foundation (Grant No. 678/13 (to A.A) and 822/12 (to S.L), the Rosetetress Trust (to A.A) and The Wolsfon Charitable Trust (to A.A and to S.L), and by a generous grant award from the Hymen Milgrom Trust (to S.L). O.Z.T is a recipient of a presidential scholarship from the University of Haifa.

Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • ARTS
  • Efferocytosis
  • Macrophage reprogramming
  • Neutrophil apoptosis
  • Resolution of inflammation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Fingerprint

Dive into the research topics of 'The pro-apoptotic ARTS protein induces neutrophil apoptosis, efferocytosis, and macrophage reprogramming to promote resolution of inflammation'. Together they form a unique fingerprint.

Cite this