The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?

Abstract

Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.

MiR-223 plays a protecting role in neutrophilic asthmatic mice through the inhibition of NLRP3 inflammasome

“…MiR-223 was reported to be emerged as a negative regulator of neutrophils activation in many experimental models of inflammatory diseases. Neutrophils were anticipated to be closely related to the underlying pathophysiology of severe asthma [48][49][50][51]. An earlier study by Johnnidis et al addressed that miR-233 played a regulatory role on neutrophil function [21], which indicated that miR-223 might exert effects on the neutrophilic asthma.…”

Inefficient N2-Like Neutrophils Are Promoted by Androgens During Infection

“…The excessive or aberrant neutrophil infiltration in the presence of high androgen levels seems to favor tissue damage and organ dysfunction not only after infection but also in non-infectious conditions ( 31 , 33 ). However, novel evidence suggests that neutrophil accumulation could also play a positive role in organ homeostasis by resolving inflammation ( 39 – 42 ), with a phenotypic characterization (i.e., pro-inflammatory vs. pro-resolving neutrophils) being necessary in order to predict the final effect of these cells on damage progression and tissue function.…”

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

“…Translational evidence incriminating neutrophils in the pathobiology of severe asthma have provided a rationale for exploring therapeutic agents that selectively block inflammatory pathways (4, 101–103). However, the precise nature of neutrophilic asthmatic inflammation remains contentious (104, 105).…”