LAUSR

Asthma is a common and complex disease, clinically defined by compatible symptomatology (wheezing and dyspnea) and reversible airflow obstruction with long-term sequelae of airway remodeling and hyperresponsiveness (1, 2). The pathogenesis of asthma is a combination of environmental and genetic factors that can lead to multiple overlapping aberrations in immune signaling. The classic etiologyofasthmaisadysfunctionalactivationofCD4 T-helper2(Th2) cells and production of type 2 cytokines (IL4, IL5, and IL13). This may occur in the setting of a deficiency in CD4Th1 signaling (3), which has been well supported in human andmouse studies where a lack of early Th1 stimulation leads to a hyperresponsive Th2 lung phenotype (4, 5). The same Th2 phenotype is common in mouse models of airway hyperreactivity and humans with asthma with intact Th1 immune systems. Patients with asthma can be subdivided into multiple overlapping subgroups, such as atopic versus nonatopic, steroid responsive versus nonresponsive, and eosinophilic versus neutrophilic asthma (3). Various non-Th2 cell types participate in the pathology, including epithelial cells, macrophages, type 2 innate lymphocytes (ILC2s) (6, 7), and iNKT cells (8), which are responsible for the cytokines IL25, IL33, andTSLP (3). They express pathogen recognition receptors, particularly TLR3, TLR7, andTLR9 (9), and respond toTLR ligands. Of particular interest are ILC2s, which have been shown to be potentproducersof type2cytokines inmousemodelsofasthma(7),and IL27,which is apotent inhibitorof this cytokineproduction in the lungs (10). Many groups have sought to rebalance Th2 and Th1 activation through skewingTh1modulation of pathogen recognition receptors as potential therapeuticapproaches forasthma(11).Althoughmanyof the preclinical trials of TLR-modifying agents have been promising, subsequent clinical trials have not yet supported their use as an asthma or allergy therapeutic. One potential reason for this failure may be the underlying heterogeneity of asthma pathogenesis. It is possible that targeting selected TLRmodulation to specific asthma immunophenotypes may lead to more effective therapeutic interventions. In this issue of the Journal, Okuzumi and colleagues (12) (pp. 309–318), building on prior evidence that the TLR7 agonist R848 (commercially available as Resiquimod) induces a strongTh1 response and limits Th2 responses, report on its role in IL33-mediated nonallergic asthma. Specifically, they investigated whether R848 could modulate IL33-induced ILC2 activation. They modeled nonallergic eosinophilic inflammationthroughrepeatedairwaystimulationofmice with I33 with an intervening treatment dose of R848 after the first dose of IL33. Treatment with R848 protected mice against many aspects of IL33-induced inflammation, reduced alveolar and tissue inflammatory cell infiltration (specifically eosinophils and ILC2s), decreased production of Th2 cytokines IL5 and IL13, and limited goblet cell hyperplasia. Notably, they did not measure airway hyperreactivity. Interestingly, themechanism of this protection appears to bemediated byremodelingof IL33-activated interstitialmacrophages (IMs) froman M2 toward anM1 phenotype rather than a direct effect of R848 on ILC2s. Abrogation of ILC2 activation appeared to be secondary to increased IL27 production by IMs, which did not occur when IL27 receptor knockout mice were treated with IL33 and R848. Taken together, the authors demonstrate a novel and complex inflammatory pathway, whereby IL33-activated IMs with anM2 phenotype can be modulated through TLR7 signaling, leading to upregulation of the antiinflammatory cytokine IL27 and abrogation of ILC2-mediated nonallergic eosinophilic inflammation (Figure 1). It must be noted that this work, although illuminating, remains very preliminary in regard to future use of R848 as a therapeutic agent for nonallergic eosinophilic asthma. Most importantly, this work was performed inmice, andconfirmatory studies inhumanswill beneeded. Second, their model used an IL33 stimulation model, which is less applicable to human asthma exacerbations, where direct viral infection is often the causative stimulus in asthmaexacerbation.Additionalwork needs to be performed to understandwhether TLR7 agonismwould be helpful in a viral upper respiratory infection trigger of asthma exacerbation. Finally, it is not clear whether themechanisms presented in this work are specific to IL33 or other cytokines that induce ILC2driven eosinophilic asthma (such as TSLP). Ultimately, in thiswork, theauthorspresent apotentiallynovel therapeutic approach to asthma that takes advantage of immunophenotyping efforts already in progress (13). One could