Gene Therapy for Occupational Lung Disease: Steering Macrophages in the Right Direction?

Pulmonary fibrosis (PF) has continued to claim the lives and lungs of those diagnosed. The immune and cellular mechanisms underpinning disease progression have proven complicated and difficult to elucidate. One patient spoke of her diagnosis, saying, “we didn’t know how to cope in the early stages. There were lots of scans and biopsies, but frustratingly more questions than answers” (1). In many ways, scientists studying PF echo the sentiments of patients. Recent work in this issue of the Journal from Zhe Zhang and colleagues (pp. 213–227) points to FcgRIIB (Fc g receptor IIb) as a possible therapeutic target and suggests that gene therapy to prevent pulmonary fibrosis may be a promising avenue for future research (2). Zhang and colleagues used a preclinical model of silicosis by instilling a silica suspension intratracheally to reliably model the pathology of a fibrosing lung condition. Silicosis is a clinically well-described interstitial lung disease stemming from the inhalation of aerosolized silica. It is often associated with workplace hazards. On spirometry, silicosis typically presents as a mixed restrictive/obstructive lung disease. On radiographs, characteristic egg-shell calcification of silica-containing nodules may be seen. Current therapies depend on presentation and consist of removing the subject from further exposure, avoiding ongoing insults, smoking cessation, and nonspecific treatments such as bronchodilators or glucocorticoids (like prednisolone) (3–5). Because of limited clinical success, several experimental therapies have been attempted. Whole lung lavage was recently promoted with some demonstrable benefit (6, 7). Furthermore, inhibition of IL-1 and TNF, as well as the use of antioxidants and inhibitors of apoptosis, have been proposed and attempted (8, 9). However, mortality from progressive fibrosis remains high without a lung transplant, which remains the best option for patients despite its limited availability and associated risks (10). Clinical silicosis studies, as well as preclinical models of the disease, have strongly implicated macrophages in disease pathogenesis, given the robust recruitment and apoptosis of macrophages in the disease (11). The subtypes of macrophages involved, and the immune signaling that results in PF and subsequent loss of lung function, are subjects of ongoing research (12). Recent reports suggest that a population of profibrotic, tissue-resident macrophages within the interstitial compartment contribute substantially to the proliferation of fibroblasts in the lung (13, 14). Research has demonstrated the existence of a signaling axis among immune-regulatory cells, interstitial macrophages, and fibroblasts. Finally, macrophage-derived exomes have been linked to the attenuation of fibrosis and improved clinical outcomes, suggesting a possible antifibrotic role for some macrophage populations (15). However, the markers of each macrophage subset, and their role in the immune response to infection and vaccination, as well as in autoimmunity and response to irritants (bleomycin, silica, etc.), demand further research. As the diverse roles of interstitial and alveolar lung macrophages become more evident, work to modulate their activity for therapeutic means is propitious. The current work by Zhang and colleagues suggests that FcgRIIB is a candidate for the modulation of inflammation, fibrosis, and the decrease in lung function after silica exposure (2). They show after silica exposure that there is consistent upregulation of Fcgr2bmRNA transcripts, as well as the protein itself, in human silicosis samples as well as in their mouse model of induced silicosis. Zhang and colleagues further show colocalization of FcgRIIB and CD68, a macrophage marker, and colocalization of FcgRIIB and Siglec F, an alveolar macrophage (AM) marker, by immunohistochemistry, thus establishing target cells for FcgRIIB action. Using single-cell RNA sequencing, they show altered transcriptional regulation in a further subset of AMs. This establishes a meaningful link between silica exposure, the expression of Fcgr2b, and FcgRIIB localization in a subset of AMs. FcgRIIB is somewhat unique among Fc receptors. Most Fc receptors express an immunoreceptor tyrosine-based activation motif in their cytoplasmic tail, but FcgRIIB encodes an immunoreceptor tyrosine-based inhibitory motif that can inhibit macrophage activation that has been shown to have a role in disease susceptibility and tolerance (16). Subsequent gene deletion experiments confirmed the antiinflammatory role they hypothesized for FcgRIIB. The authors probed the function of FcgRIIB by examining how its absence, globally induced using an Fcgr2b mouse, impacted markers of inflammation, fibrosis, and lung function after either intratracheal silica installation or vehicle control. They show that wild-type mice exposed to silica develop significant deficits in lung function, increased markers of inflammation, and more histologically observable fibrosis and inflammation than those treated with the vehicle alone. Furthermore, Fcgr2b mice exposed to silica fared significantly worse with higher degrees of inflammatory markers, and they exhibited a greater degree of lung inflammation and fibrosis histologically. To better understand the cell-intrinsic effects of FcgRIIB, they replicated the above findings in