Biological Roles of Neutrophil-Derived Granule Proteins and Cytokines Marco Antonio Cassatella, Nataliya K. Östberg, Nicola Tamassia, Oliver Soehnlein  Trends in Immunology  Volume 40, Issue 7, Pages 648-664 (July 2019) DOI: 10.1016/j.it.2019.05.003 Copyright © 2019 Elsevier Ltd Terms and Conditions

Figure 1 Key Figure. Proteomics of Human Neutrophil Compartments. Internal (intracellular) and external (released and exposed on the cell surface) proteins from neutrophil subproteomes have been investigated. The internal subproteome is represented by a neutrophil cytoskeleton study [17]. Upon inflammation, neutrophils release a variety of mediators, including proteins, reactive oxygen species (ROS), and lipid mediators (forming the so-called, secretome [22]). They also externalize a number of proteins to the cell plasma membrane. Neutrophil external subproteomes have been studied more explicitly, perhaps because of their importance in inflammatory processes; these include investigations of cell plasma membrane proteins [15], cytonemes [20,21], NETomes [23,25], and extracellular vesicles [26] (the examples of protein representatives for these groups are listed in boxes). Granular proteins and cytokines are discussed in this review in more detail and thus are not specified in the figure (marked in single quotes). Abbreviations: GADPH, glyceraldehyde 3-phosphate dehydrogenase; MMP9, matrix metalloproteinase 9. Trends in Immunology 2019 40, 648-664DOI: (10.1016/j.it.2019.05.003) Copyright © 2019 Elsevier Ltd Terms and Conditions

Figure 2 Epigenetic Landscapes Can Condition Differential Cytokine Gene Expression Profiles in Human Neutrophils versus Monocytes. ChIP-seq snapshots for CXCL8 (below the green open lock) show that PU.1 and H3K27Ac peaks are already present in resting human neutrophils and monocytes, indicating that their CXCL8 locus is constitutively accessible. This may explain why rapid transcription of CXCL8 mRNA can occur in neutrophils and monocytes stimulated with lipopolysaccharide (LPS) or R848. By contrast, ChIP-seq snapshots of the IL6 locus in neutrophils illustrate locus inaccessibility at steady-state. However, with appropriate stimulation [by toll-like receptor (TLR)4 or TLR8 ligands] PU.1 initiates chromatin accessibility, favoring the binding of activated transcription factors (not shown), H3K27Ac deposition, and ultimately, IL6 transcription. The latter, however, is more delayed than in activated monocytes because chromatin (IL6 locus) in these cells is already constitutively open (ChIP-seq snapshots below the green open lock). Finally, ChIP-seq snapshots of the IL10 locus in neutrophils (below the red closed lock) show inaccessible regulatory regions, as shown by the absence of PU.1 and H3K27Ac, even after TLR stimulation. By contrast, the IL10 locus of monocytes displays PU.1 and H3K27Ac deposition, similar to what is observed at the CXCL8 locus, leading to prompt IL10 transcription upon stimulation. Data are from [115,116]. Trends in Immunology 2019 40, 648-664DOI: (10.1016/j.it.2019.05.003) Copyright © 2019 Elsevier Ltd Terms and Conditions