Inflammation Gets on the Lung's Nerves: IL-17 and Neuroendocrine Cells Mediate Ozone Responses in Obesity.

Most lung diseases result from the interaction of environmental exposures with host biology. It is therefore logical to assume that the increasing prevalence of chronic lung diseases, such as asthma, may be due to increasingly pervasive environmental exposures (e.g., through human activity and climate change) interacting with altered human biology (e.g., through diet-induced obesity). Ozone is an important trigger of lung disease exacerbations. Well-conducted epidemiological studies have suggested that ozone leads annually to approximately 800 deaths, 4,500 hospitalizations, and . 1 million restricted-activity days, at a cost of $5 billion (1, 2), in the United States alone. The U.S. Environmental Protection Agency stated that due to climate change, the levels and effects of ozone will increase substantially (3). Concurrently, obesity has become a global epidemic and is clearly associated with changes in lung physiology and responses to injuries (4). The potential overlap between these two significant public health concerns has led researchers to explore the effects of obesity in ozone-induced lung inflammation and airway hyperresponsiveness (AHR). The study in this issue of the Journal by Mathews and colleagues (pp. 341–351) builds upon this expanding body of research (5). The authors started from the observation that both ozone exposure and obesity increase lung levels of IL-17A, a cytokine that is strongly implicated in the pathogenesis of asthma (6). They observed in mice that obesity (both geneand dietinduced) amplified IL-17 induction after ozone exposure, and that IL-17 accounted for a significant part of the obesity-induced increase in neutrophilia and AHR observed after ozone exposure. Furthermore, they identified gastrin-releasing peptide (Grp), a product of airway neuroendocrine cells, as an important contributor to obesity-amplified, ozone-induced lung injury downstream of IL-17. Both Grp and its receptor Grpr were increased in lung tissue of obese mice after ozone exposure, and contributed to the increased neutrophilia and AHR. Although IL-17A blockade did not decrease Grp levels, it did decrease expression of Grpr. The data presented by Mathews and colleagues open up exciting research avenues. IL-17A is now recognized as an important driver of asthma pathogenesis, particularly in severe, treatmentresistant cases (6). The recognition that both endogenous (i.e., obesity) and exogenous (i.e., ozone exposure) factors synergistically induce IL-17 in the lung raises the question as to whether these factors influence the development and establishment of an IL-17–predominant asthma endotype. In addition, we may also ask whether other environmental exposures or medical conditions contribute to exacerbated asthma endotypes. We may also consider such factors in a precision-medicine approach to asthma treatment: perhaps patients with asthma and the IL-17 endotype may benefit particularly from weight loss and should be vigilant against exposure to pollutants like ozone. Another exciting finding is the recognition of Grp as a participant in ozone-obesity–mediated lung injury. Grp is expressed by pulmonary neuroendocrine cells (PNECs), which are known to have an oxygen-sensing capacity and release Grp in response to ozone (7). Very little is known about the cross-talk between the immune system and the neuroendocrine system in the lung, although emerging evidence suggests there is a connection (8). Grp is only one of several peptides released from PNECs. Barrios and colleagues recently reported that mucus hypersecretion after allergen challenge required neural stimulation of PNECs (9), suggesting a connection of PNECs to asthma. The present data suggest a specific role for Grp; however, greater insight into the function of PNECs may also enhance our understanding of asthma pathogenesis and the link to obesity and environmental exposures. Currently, the effects of obesity, asthma, and ambient pollution on the abundance and function of PNECs are largely unknown. Several questions remain unanswered by this work. For example, we are not told about the cellular source of IL-17 or the target of its actions. In a model of obese mice with asthma, IL-17–producing type 3 innate lymphoid cells were found to be responsible for increased AHR, and the NLRP3 inflammasome also contributed to obesity-induced asthma (10). NLRP3 also plays a role in ozone-induced lung injury (11). Whether the inflammasome synergizes with IL-17 in the obesity-ozone response is unknown. Similar questions apply to the Grp axis. According to this work, expression of Grp is not affected by IL-17A blockade, but expression of the receptor is diminished. This may mean that the targets of IL-17 are not the neuroendocrine cells themselves, but their downstream effectors. Many lung cell types, including fibroblasts, myocytes, and immune cells, express Grpr. It is possible that ozone exposure activates IL-17 and neuroendocrine cells in tandem, and IL-17 serves to enhance Grp effects by upregulating Grpr expression and thus the sensitivity to neuroendocrine signals. Future research will need to clarify these issues. Some caveats to this study need to be highlighted, and at the same time raise further research questions. The authors used only female mice for their studies. The Grpr gene is located on the X chromosome, as the authors point out in their discussion. Thus, further study is needed to investigate the applicability of these findings to males. By the same token, ozone-induced lung-function decrements are greater in obese women than in obese men (12), and increased body mass index is predictive of asthma incidence in women, but not in men (13). Thus, a comparison between male and female Grpr responses to ozone in the context of obesity would be informative regardless of the outcome. Furthermore, Grpr is not the only Grp receptor (7), and therefore this study may