Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Abstract

Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI).

Keywords: margination; metabolism; scavenging; stress response; transcription.

Figure 1

Overview of neutrophil recruitment and response in the lung. As a major neutrophil reservoir, the lungs are an important environment in the study of neutrophil biology, both at homeostasis and in responding to inflammatory stimuli. (a) Endothelial cells upregulate P-selectin to bind P-selectin glycoprotein ligand-1 on circulating naive neutrophils. Upon slowing down, neutrophil β2 integrin binds with higher affinity to ICAM-1 on the endothelial cell surface followed by extravasation into the tissue. (b) Recruited neutrophils recognize pathogen-associated molecular patterns from all types of pathogens by surface pattern recognition receptors. Phagocytosed pathogens are degraded internally by fusion of the granules with the phagosome. (c) Neutrophils quickly apoptose and are cleared by tissue macrophages. (d) Neutrophil recruitment can also lead to alternate fates. Dysregulated neutrophil responses in diseases such as CF and COPD include the GRIM (granule releasing, immunomodulatory, and metabolically active) phenotype which exhibits active degranulation but impaired pathogen clearance. The release of NE damages host tissue while sustained CXCL8 production drives further neutrophil recruitment. Neutrophils can also expel their DNA through NETosis, but may survive and retain phagocytic capability.

Figure 2

Neutrophil responses to viral infection. Neutrophils have an important role in antiviral immunity. (a) Neutrophils are recruited to sites of viral infection in the lung via signaling through MyD88 and TRIF. Interleukin-1β production by the NLRP3 inflammasome in resident antigen presenting cells drives recruitment. (b) once in the tissue, MAVS signaling initiates neutrophil activation and production of inflammatory mediators. Neutrophils engulf antibody-bound virions via surface Fc receptors. (c) The inhibitory receptor LAIR-1 binds collagen and suppresses neutrophil activity. (d) Transcriptional regulators such as BCL6 suppress apoptosis and represent a potential target for enhancing neutrophil-mediated antiviral immunity.