Cytokine production by human neutrophils: Revisiting the “dark side of the moon”

Abstract

Polymorphonuclear neutrophils are the most numerous leucocytes present in human blood, and function as crucial players in innate immune responses. Neutrophils are indispensable for the defence towards microbes, as they effectively counter them by releasing toxic enzymes, by synthetizing reactive oxygen species and by producing inflammatory mediators. Interestingly, recent findings have highlighted an important role of neutrophils also as promoters of the resolution of inflammation process, indicating that their biological functions go well beyond simple pathogen killing. Consistently, data from the last decades have highlighted that neutrophils may even contribute to the development of adaptive immunity by performing previously unanticipated functions, including the capacity to extend their survival, directly interact with other leucocytes or cell types, and produce and release a variety of cytokines. In this article, we will summarize the main features of, as well as emphasize some important concepts on, the production of cytokines by human neutrophils.

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

“…Neutrophil‐derived cytokines not only regulate inflammation and immunity, but also orchestrate a variety of physiologic processes such as hematopoiesis, angiogenesis, and fibrogenesis, as well as pathologic conditions such as infectious, inflammatory, autoimmune, or neoplastic diseases . Circulating blood neutrophils from healthy individuals do not normally express cytokines, but can generate them in response to stimulus‐specific environmental signals . Many ligands can activate cytokine expression by human neutrophils, for instance microbial factors such as pathogen‐associated molecular patterns (PAMPs) binding to pattern recognition receptors (PRR), including TLRs, RIG‐I and DNA sensors, or host‐generated cytokines.…”

“…Neutrophils are currently recognized as potential sources of cytokines, including chemokines and growth factors. 1 Neutrophil-derived cytokines not only regulate inflammation and immunity, but also orchestrate a variety of physiologic processes such as hematopoiesis, angiogenesis, and fibrogenesis, as well as pathologic conditions such as infectious, inflammatory, autoimmune, or neoplastic diseases. [2][3][4] Circulating blood neutrophils from healthy individuals do not normally express cytokines, but can generate them in response to chromatin remodeling.…”

Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: Subversion towards autoimmunity by proteinase 3

“…It is notable that insufficient clearance of apoptotic neutrophils may lead to the release of neutrophil‐derived inflammatory mediators. Neutrophils are capable of expressing, storing within intracellular pools and secreting cytokines including B‐cell‐activating factor (BAFF), TNF‐related apoptosis‐inducing ligand (TRAIL), CXCL8, CCL20 and interleukin (IL) 1 receptor antagonist (IL1‐ra) . Whereas IL‐1ra, CXCL8 and CXCL2 were already detected in resting cells, preformed cytokines present in the cytosol of mature human neutrophils, such as IL‐16C and MIF, can be released during secondary necrosis .…”

“…Neutrophils are capable of expressing, storing within intracellular pools and secreting cytokines including B-cell-activating factor (BAFF), TNFrelated apoptosis-inducing ligand (TRAIL), CXCL8, CCL20 and interleukin (IL) 1 receptor antagonist (IL1ra). 85,86 Whereas IL-1ra, CXCL8 and CXCL2 were already detected in resting cells, preformed cytokines present in the cytosol of mature human neutrophils, such as IL-16C and MIF, can be released during secondary necrosis. 87 Experimentally, several treatments could be applied to PR3expressing cells to mimic PR3-induced apoptotic cells.…”

Differential and sequential immunomodulatory role of neutrophils and Ly6Chiinflammatory monocytes during antiviral antibody therapy

“…While the role of IC-activated DCs in the enhancement of antiviral immune responses has been addressed in several studies (Lambour et al, 2016; Wang et al, 2019; Wen et al, 2016) the role of IC-activated neutrophils has mostly been overlooked. Evidence shows that neutrophils, in addition to being key effector cells to fight against invading pathogens, are also endowed with immunomodulatory properties through the secretion of a plethora of chemokines and cytokines (Mantovani et al, 2011; Tamassia et al, 2018; Tecchio and Cassatella, 2016). Yet, the functional activation of neutrophils by viral ICs and the resulting effect on their immunomodulatory properties have poorly been studied in the context of antiviral mAbs therapies.…”