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SummaryControversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-β-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.

During the resolution of inflammation macrophages undergo functional changes upon exposure to pro-resolving agents in their microenvironment. Primarily, engulfment of apoptotic polymorphonuclear (PMN) cells promotes conversion of macrophages toward a pro-resolving phenotype characterized by reduced CD11b expression. These macrophages are not phagocytic, do not respond to TLR ligands, and express relatively high levels of the pro-resolving enzyme 12/15-lipoxygenase (LO). Here, we report that the immuno-regulatory lectin galectin-1 is selectively expressed by CD11bhigh, but not CD11blow macrophages. Upon exposure in vivo and ex vivo, galectin-1 directly promoted macrophage conversion from a CD11bhigh to a CD11blow phenotype and up-regulated the expression and activity of 12/15-LO. Moreover, galectin-1 treatment in vivo promoted the loss of phagocytic capacity (efferocytic satiation) in peritoneal macrophages and down-regulated secretion of TNF-α, IL-1β, and IL-10 upon LPS exposure. Our results suggest that galectin-1 could be an essential mediator in the control of macrophage function during the resolution of inflammation. Fil: Rostoker, Ran. University of Haifa. Faculty of Natural Sciences. Departament of Biology; Israel; Fil: Yaseen, Hiba. University of Haifa. Faculty of Natural Sciences. Departament of Biology; Israel; Fil: Schif Zuck, Sagie. University of Haifa. Faculty of Natural Sciences. Departament of Biology; Israel; Fil: Lichtenstein, Rachel G.. Ben-Gurion University. Department of Biotechnology Engineering; Israel; Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Universidad de Buenos Aires. Facultad de Cs.exactas y Naturales. Departamento de Quimica Biologica; Argentina; Fil: Amiram, Ariel. University of Haifa. Faculty of Natural Sciences. Departament of Biology; Israel

The physiological resolution of a well-orchestrated inflammatory response is essential to maintain homeostasis. Therefore, gaining a comprehensive understanding in molecular terms of the events that direct the termination of acute inflammation is imperative. Recently, new families of local-acting mediators were discovered that are biosynthesized from the essential fatty acids eicosapentaenoic acid and docosahexaenoic acid. These new chemical mediators are endogenously generated in inflammatory exudates collected during the resolution phase, and were termed resolvins and protectins because specific members of these families control the magnitude and duration of inflammation in animals. In addition, recent results indicate novel actions of resolvins and protectins in removing chemokines ferried from the tissue by apoptotic neutrophils and T cells during resolution. Here, we review recent advances on the biosynthesis and actions of these novel anti-inflammatory and proresolving mediators.