Regulatory mechanisms of neutrophil migration from the circulation to the airspace

Abstract

The neutrophil, a short-lived effector leukocyte of the innate immune system best known for its proteases and other degradative cargo, has unique, reciprocal physiological interactions with the lung. During health, large numbers of ‘marginated’ neutrophils reside within the pulmonary vasculature, where they patrol the endothelial surface for pathogens and complete their life cycle. Upon respiratory infection, rapid and sustained recruitment of neutrophils through the endothelial barrier, across the extravascular pulmonary interstitium, and again through the respiratory epithelium into the airspace lumen, is required for pathogen killing. Overexuberant neutrophil trafficking to the lung, however, causes bystander tissue injury and underlies several acute and chronic lung diseases. Due in part to the unique architecture of the lung’s capillary network, the neutrophil follows a microanatomic passage into the distal airspace unlike that observed in other end-organs that it infiltrates. Several of the regulatory mechanisms underlying the stepwise recruitment of circulating neutrophils to the infected lung have been defined over the past few decades; however, fundamental questions remain. In this article, we provide an updated review and perspective on emerging roles for the neutrophil in lung biology, on the molecular mechanisms that control the trafficking of neutrophils to the lung, and on past and ongoing efforts to design therapeutics to intervene upon pulmonary neutrophilia in lung disease.

Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States

“…Among these are genes that code for chemokines and chemokine receptors that attract both lymphocytes and myelocytes to inflammation sites (CCL20, CCL2, CXCR1, CXCR3, CXCL8) [ 60 , 61 ], pro-inflammatory cytokines and cytokine receptors (IL-1B, IL-1R1, NFKB1, IFNG, IL-6, TNF) [ 62 , 63 ] that promote the activation of immune cells, and several proteins/granules with antimicrobial activity (MPO [ 64 ], AZU1 [ 65 ], ELANE [ 66 , 67 ], DEFA4 [ 68 ]). Moreover, there are metalloproteinases (MMP8 and MMP9) involved in the degradation of the extracellular matrix (ECM) to facilitate neutrophil migration [ 69 , 70 ] into the airways and in the regulation of cytokine activity. Of note, hierarchical clustering analysis of these genes indicated a cross-study grouping of closely functional-related molecules.…”

Corynebacterium Species Inhibit Streptococcus pneumoniae Colonization and Infection of the Mouse Airway

“…These increases parallel the elevated MCP-1, which mobilizes the recruitment of inflammatory monocytes from the bone marrow ( Gschwandtner et al, 2019 ), detected in the BAL of Corynebacterium -infected mice. Neutrophils are also recruited to the lung from the bone marrow, though responses to other chemokines such as MIP-1 (CXCL2) ( Lin and Fessler, 2021 ) were not measured here. In contrast, the lungs of mice infected with C. accolens or C. amycolatum had reduced alveolar macrophages (AMs, CD45 + SiglecF + CD11b low CD11c + cells), compared with PBS treated controls ( Figure 3E ).…”

Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

“…Among these are genes that code for chemokines and chemokine receptors that attract both lymphocytes and myelocytes to inflammation sites (CCL20, CCL2, CXCR1, CXCR3, CXCL8) [60,61], pro-inflammatory cytokines and cytokine receptors (IL-1B, IL-1R1, NFKB1, IFNG, IL-6, TNF) [62,63] that promote the activation of immune cells, and several proteins/granules with antimicrobial activity (MPO [64], AZU1 [65], ELANE [66,67], DEFA4 [68]). Moreover, there are metalloproteinases (MMP8 and MMP9) involved in degradation of extracellular matrix (ECM) to facilitate neutrophil migration [69,70] into the airways and in the regulation of cytokine activity. Of note, hierarchical clustering analysis of these genes indicated a cross-study grouping of closely functional-related molecules.…”