Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells

Abstract

Neutrophils and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) share origin and many morphological and phenotypic features. However, they have different biological role. Neutrophils are one of the major mechanisms of protection against invading pathogens, whereas PMN-MDSC have immune suppressive activity and restrict immune responses in cancer, chronic infectious disease, trauma, sepsis, and many other pathological conditions. Although in healthy adult individuals, PMN-MDSC are not or barely detectable, in patients with cancer and many other diseases they accumulate at various degree and co-exist with neutrophils. Recent advances allow for better distinction of these cells and better understanding of their biological role. Accumulating evidence indicates PMN-MDSC as pathologically activated neutrophils, with important role in regulation of immune responses. In this review, we provide an overview on the definition and characterization of PMN-MDSC and neutrophils, their pathological significance in a variety of diseases, and their interaction with other stromal components.

Keywords: Cancer; Fibroblasts; Infectious diseases; Myeloid-derived suppressor cells; Neutrophils.

Figure 1. Sequential steps of neutrophil migration on endothelial and epithelial cells

A. A neutrophil migration on endothelial cells consists of the following steps: 1) binding of neutrophils to endothelial cells depends on the transient interaction of P- and E-selectins with their ligands, such as P-selection glycoprotein ligand (PSGL)-1, L-selectin and CD44; 2) rolling and slow rolling along the vessel wall depend on selectins and integrins (β2 and β1 integrins); 3) the interaction between activated integrins and their ligands (primarily ICAM-1 and ICAM-2) results in the firm neutrophil arrest on the endothelium; 4) crawling of neutrophils follows the chemokine gradient along the endothelium, which leads them to the preferential sites of transmigration; 5) transmigration of neutrophils via endothelial cell-cell junctions (paracellular transmigration) or through the endothelium (transcellular transmigration). B. For neutrophil migration across epithelia, the process contains three sequential steps: adhesion, migration, and post-migration stage. Neutrophil transepithelial migration starts with adhesion of the neutrophils to the basolateral epithelial membrane, which is supported by ligation of CD11b/CD18 on the neutrophil surface to several molecules on the epithelial surface including fucosylated glycoproteins, JAM-C. After adhesion, neutrophils crawl along the epithelial cell membrane through sequential binding to several epithelial cell surface molecules, such as CD47 (binding to SIRPα). Tight junction between neutrophil and epithelium requires binding of JAML to epithelial CAR. After neutrophils completely go through the epithelial monolayer, they adhere to the apical epithelial surface mediated by the binding of the FcR to apical antigens, binding of CD11b/CD18 to ICAM-1, and likely binding of DAF to CD97.

Figure 2. Neutrophils/PMN-MDSC crosstalk with stromal cells under pathological conditions

Under inflammatory conditions, neutrophils crosstalk with endothelial cells and fibroblasts involves: (a) neutrophils release soluble factors, which on one hand protect endothelial cells like proteinase 3; on the other hand, they produce heparin-binding protein, ROS and MPO that damage the barrier integrity. (b) neutrophils release NETs or elastase to promote fibroblast differentiate into myofibroblasts, leading to lung fibrosis; (c) or they release S100A8/A9 proteins to activate cardiac fibroblasts and causes cardiac inflammation and fibrosis. PMN-MDSC, which have a high level of ROS and MPO, may also contribute to the tissue damage during their trafficking. In cancers, tumor cells inhibit the release of CXCL1 and other neutrophil chemokines by carcinoma-associated fibroblasts via production of CSF1/M-CSF, resulting in the impaired migration of neutrophils and PMN-MDSC. NETs: neutrophil extracellular traps. CAF: carcinoma-associated fibroblasts.