Role of neutrophils in innate immunity: a systems biology-level approach

Abstract

The innate immune system is the first line of host defense against invading microorganisms. Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential to the innate immune response against invading pathogens. Compared with the acquired immune response, which requires time to develop and is dependent on previous interaction with specific microbes, the ability of neutrophils to kill microorganisms is immediate, non-specific, and not dependent on previous exposure to microorganisms. Historically, studies on PMN-pathogen interaction focused on the events leading to killing of microorganisms, such as recruitment/chemotaxis, transmigration, phagocytosis, and activation, whereas post-phagocytosis sequelae were infrequently considered. In addition, it was widely accepted that human neutrophils possessed limited capacity for new gene transcription and thus, relatively little biosynthetic capacity. This notion has changed dramatically within the past decade. Further, there is now more effort directed to understand the events occurring in PMNs after killing of microbes. Herein we review the systems biology-level approaches that have been used to gain an enhanced view of the role of neutrophils during host-pathogen interaction. We anticipate that these and future systems-level studies will ultimately provide information critical to our understanding, treatment, and control of diseases caused by pathogenic microorganisms.

Fig. 1

Overview of neutrophil functions / processes that have been investigated using proteomics (indicated by 2-D gel) or transcriptomics (indicated with a cDNA microarray). See text for details.

Fig. 2

Neutrophil phagocytosis and microbicidal process. Panel A illustrates binding and phagocytosis of a microbe opsonized with antibody or serum complement. Phagocytosis triggers production of superoxide (O₂^˙−) from which other secondarily derived ROS are formed, including hydrogen peroxide (H₂O₂) and hypochlorous acid (HOCl). Panel B is a transmission electron micrograph of a human neutrophil that has phagocytosed numerous Staphylococcus aureus (Microbe).

Fig. 3

Neutrophil apoptosis. Human neutrophils were isolated from venous blood and then processed for transmission electron microscopy or stained with Wright-Giemsa (inset) after purification (0 h) or 24 h in culture.

Fig. 4

Neutrophil apoptosis differentiation program. Post-phagocytosis sequelae identified using microarray-based approaches followed by in vitro assays with human neutrophils. The neutrophil apoptosis differentiation program represents a final stage of transcriptionally regulated PMN maturation that is accelerated by phagocytosis.

Fig. 5

A schematic that illustrates two fundamental outcomes of microbe-neutrophil interaction. See text for details.

Fig. 6

Comparison of transcript levels in PMNs and peripheral blood mononuclear cells (PBMCs) from patients with HIES and control subjects. Principal component analysis of baseline transcript levels in PMNs (A) or PBMCs (B) from control subjects and patients. C) Transcripts increased (yellow) or decreased (blue) in patient leukocytes. D) A modified Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com) of the PMN microarray data indicating relative changes in transcripts encoding molecules involved in interferon and STAT signal transduction. Yellow nodes indicate transcripts that are increased and blue nodes indicate transcripts that are decreased in HIES patient PMNs. Adapted from Fig. 2 of the Supplementary Appendix of Holland et al. [4].