Update on Neutrophil Function in Severe Inflammation

Abstract

Neutrophils are main players in the effector phase of the host defense against micro-organisms and have a major role in the innate immune response. Neutrophils show phenotypic heterogeneity and functional flexibility, which highlight their importance in regulation of immune function. However, neutrophils can play a dual role and besides their antimicrobial function, deregulation of neutrophils and their hyperactivity can lead to tissue damage in severe inflammation or trauma. Neutrophils also have an important role in the modulation of the immune system in response to severe injury and trauma. In this review we will provide an overview of the current understanding of neutrophil subpopulations and their function during and post-infection and discuss the possible mechanisms of immune modulation by neutrophils in severe inflammation.

Keywords: CD64; infection; innate immunity; neutrophils; severe inflammation; trauma.

Figure 1

Neutrophils generation. Granulopoiesis or neutrophil generation occur in the bone marrow. At the first step, a self-renewing hematopoietic stem cell (HSC) differentiate to a multipotent progenitor (MPP) cell. Then MPP differentiate to lymphoid-primed multipotent progenitors (LPMP), which give rise into granulocyte-monocyte progenitors (GMP). After that, GMP cells turn in to myeloblast and posses through a maturation process including promyelocyte, myelocyte, metamyelocyte, band cell, and finally will commit to generate the mature neutrophils.

Figure 2

Schematic review of neutrophil extravasation cascade. The process of neutrophil migration begins with neutrophil “tethering to” the endothelium of blood vessels in steps (1) rolling, (2) adhesion, and (3) crawling, firm adhesion and patrolling. (4) Trans endothelial migration occurs after approaching the site of inflammation where they cross the blood vessel wall in an extravasation step in which neutrophils travel along the endothelial basement membrane until finding a small gap between pericytes. They start migrating through the space by forming a protruding uropod which allows neutrophils to access to the inflamed area. Microparticle formation occurs following uropod formation which is shown to have pivotal role in controlling vascular permeability.

Figure 3

Activation of immune response after trauma. Activation of neutrophils after trauma evokes the development of a local inflammatory response. If this local inflammatory response becomes excessive this may lead to a systemic inflammatory response (SIRS) and multiple organ dysfunction syndrome (MODS). To restore the equilibrium to a favorable state, a compensatory anti-inflammatory response (CARS) may occur or, alternatively, the pro-inflammatory and anti-inflammatory responses may counteract leading to a mixed antagonist response (MARS).

Figure 4

INF-gamma induced the expression of Fc gamma receptor (CD64). IFN-γ induces its receptor and the downstream signaling pathways including JAKs and the STAT family of transcription factors. STAT dimers enhance the transcription of CD64 gene and the translated CD64 will be targeted in to the plasma membrane bilayer lipid.