The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease

Abstract

Neutrophils are crucial innate immune cells and comprise 50–70% of the white blood cell population under homeostatic conditions. Upon infection and in cancer, blood neutrophil numbers significantly increase because of the secretion of various chemo- and cytokines by, e.g., leukocytes, pericytes, fibroblasts and endothelial cells present in the inflamed tissue or in the tumor microenvironment (TME). The function of neutrophils in cancer has recently gained considerable attention, as they can exert both pro- and anti-tumorigenic functions, dependent on the cytokine milieu present in the TME. Here, we review the effect of cytokines on neutrophil development, tissue homing, function and plasticity in cancer and autoimmune diseases as well as under physiological conditions in the bone marrow, bloodstream and various organs like the spleen, kidney, liver, lung and lymph nodes. In addition, we address several promising therapeutic options, such as cytokine therapy, immunocytokines and immunotherapy, which aim to exploit the anti-tumorigenic potential of neutrophils in cancer treatment or block excessive neutrophil-mediated inflammation in autoimmune diseases.

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

“…For example, G-CSF/CSF-3 is a pro-inflammatory cytokine involved in neutrophil differentiation and systemic mobilization and has been implicated in the pathogenesis of neutrophilic atopic asthma. 46,56 Several preclinical studies in asthma models showed that blockage of upstream inductors or the receptor of G-CSF/CSF-3 reduced circulating cytokine levels, alleviated the airway inflammatory response, and improved disease outcome. 46–48,57 Furthermore, G-CSF/CSF-3 levels in the sputum of asthma patients have been suggested as a marker of airway neutrophilic inflammation.…”

Single dose of peg GCSF compared with daily GCSF in de novo acute myeloid leukemia patients on high dose cytarabine consolidation chemotherapy (HIDAC)

“…In the bone marrow, GCSF is involved in not only neutrophil differentiation, but also plays a key role in the release of neutrophils from the bone marrow into the circulation [14]. GCSF is essential to regulate neutrophil production in a "steady -state" situation to maintain the neutrophil level in a narrow normal range [15].…”

Neutrophils only die twice

“…Neutrophils are the first immune cells recruited from the blood to fight infection ( 1 ). They actively defend against pathogens in multiple ways, including by eating microbes, killing them with reactive oxygen, and by releasing inflammatory signals ( 1 ).…”

“…Neutrophils are the first immune cells recruited from the blood to fight infection ( 1 ). They actively defend against pathogens in multiple ways, including by eating microbes, killing them with reactive oxygen, and by releasing inflammatory signals ( 1 ). Neutrophils are an extremely toxic immune cell, even to themselves, and therefore have a limited life span—they are primed to die ( 1 ).…”

“…They actively defend against pathogens in multiple ways, including by eating microbes, killing them with reactive oxygen, and by releasing inflammatory signals ( 1 ). Neutrophils are an extremely toxic immune cell, even to themselves, and therefore have a limited life span—they are primed to die ( 1 ). However, even in their lifeless state, neutrophils continue to fight infection.…”