Galectin-1 Facilitates Macrophage Reprogramming and Resolution of Inflammation Through IFN-β.

Hiba Yaseen,Amiram Ariel,Juan Manuel Pérez-Sáez,Sergei Butenko,Sagie Schif-Zuck,Irina Polishuk-Zotkin,Gabriel Adrian Rabinovich

doi:10.3389/fphar.2020.00901

Abstract

During the resolution of acute inflammation, macrophages undergo reprogramming from pro-inflammatory, to anti-inflammatory/reparative, and eventually to pro-resolving macrophages. Galectin-1 (Gal-1) is a bona fide pro-resolving lectin while interferon β (IFN-β) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1null mice exhibit a hyperinflammatory phenotype during the resolution of zymosan A-induced peritonitis but not during the early inflammatory response. This phenotype was characterized by reduced macrophage numbers, increased secretion of pro-inflammatory cytokines, such as interleukin-12 (IL-12), and reduced secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10). In addition, we found a delayed expression of the pro-resolving enzyme 12/15-lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1null mice. Moreover, we observed sex-dependent differences in the inflammatory profile of Gal-1null mice. Notably, we found that IFN-β levels were reduced in resolution-phase exudates from Gal-1null mice. Administration of IFN-β in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1null mice. In particular, IFN-β recovered a subset of F4/80+GR-1+ macrophages, restored IL-12 and IL-10 secretion from macrophages to WT values and diminished abnormal peritoneal PR3 levels in Gal-1null mice. In conclusion, our results revealed a new Gal-1-IFN-β axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

Highlights

Inflammation is a beneficial host response to foreign challenges or tissue injury that, when resolved in an effective and timely manner, leads to the restoration of tissue homeostasis (Filep, 2013; Sugimoto et al, 2019)
Using a spontaneously resolving model of zymosan A-induced peritonitis (Bannenberg et al, 2005; Cash et al, 2009), we detected upregulation of Gal-1 expression in peritoneal fluids and in isolated F4/80+ monocytes/macrophages, which peaked at 48 h post-peritonitis initiation (PPI), and declined afterwards (Figures 1A–D and Supplementary Material, Figures S1A, B)
The coordinated increase in Gal-1 levels in peritoneal fluids and F4/80+ macrophages is in accord with previous reports (Rostoker et al, 2013; Law et al, 2020), and suggests that macrophages are the major cell population responsible for Gal-1 secretion and peritoneal levels during the resolution of inflammation

Summary

Introduction

Inflammation is a beneficial host response to foreign challenges or tissue injury that, when resolved in an effective and timely manner, leads to the restoration of tissue homeostasis (Filep, 2013; Sugimoto et al, 2019). The active resolution of a localized acute inflammation culminates in the elimination of short-lived neutrophils by resolution-phase macrophages and the return of leukocyte cell populations to homeostatic numbers (Ariel and Serhan, 2012; Ariel and Timor, 2013; Greenlee-Wacker, 2016; Dalli and Serhan, 2017; Elliott et al, 2017). The clearance of apoptotic neutrophils leads to the reprogramming of resolution-phase macrophages to a distinct satiated/pro-resolving phenotype that is highlighted by the loss of its phagocytic properties and the departure of the injury site (Ariel and Serhan, 2012; Greenlee-Wacker, 2016; Elliott et al, 2017). Eosinophils are key cellular effectors in the resolution of inflammation (Yamada et al, 2011; Isobe et al, 2012)

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Conclusion