Nowhere in biomedical research does a cell type seem as simultaneously vital and vexing as the neutrophil. Human immunity deteriorates rapidly in the absence of neutrophils whereas their dysfunctional abundance can cause misery and harm, as exemplified by cystic fibrosis (CF), neutrophilic asthma, and chronic obstructive pulmonary disorders (COPDs). The goal of treating the underlying causes of these diseases without impairing immunity has been elusive, leading to calls for improved understanding of neutrophil plasticity and the possibility that it enables generation of pathological neutrophil subsets. 1, 2 To this end, Forrest, Tirouvanziam, and colleagues report development of a tissue culture method that recreates several of the pathological phenotypes observed in airway neutrophils from CF patients, summarized by the memorable acronym “GRIM” for their granule-releasing, immunoregulatory, and metabolic attributes. Among the most intriguing and important aspects of their study is its demonstration of microenvironment as a determinant of functional responsiveness in human neutrophils, an epigenetic plasticity previously suspected as a contributor to CF2 and other inflammatory diseases. 3

New assays involving cultured human cells are a welcome addition to the existing animal models used in preclinical drug testing. This is because most, 80%, of all drugs that show promise in mouse or other animal studies go on to fail in phase I or II human clinical trials. 4 Numerous conceptual advances in immunology have been made using mice, 5 but it seems our species are not sufficiently alike to consistently predict clinical success. One recent comparison of neuro-inflammatory pathways undertaken to understand the high rate of failure of anti-inflammatory treatments for Alzheimer’s disease6 found that whereas up to 60% of inflammatory cell or cytokine interactions were similar in mouse and humans, 10–15% were “reversed.” The remaining interactions that were evaluated were unique to humans, with no known counterparts in the mouse. That additional methods of preclinical testing are needed should not be surprising given the estimated 100 million year evolutionary distance between rodents and humans. 7 The report from Forrest et al. thus adds a potentially important tool to the drug development toolbox, as well as further evidence of neutrophil plasticity that is reshaping perceptions about their functionally dynamic responsiveness in health and disease.