Studies of the underlying cause or causes of chronic
rhinosinusitis (CRS) over the past 20 or more years have expanded from a focus on systemic immune and allergic mechanisms to an intense search for the underlying drivers of mucosal
inflammation. These drivers involve mucosal inflammatory pathways that become activated by
allergens, microbial stimuli, or poorly understood exogenous or endogenous stimuli. The holy grail in the study of CRS is to identify specific drivers of mucosal
inflammation and translate these into more effective treatment for CRS. Certain deficiencies in local innate immunity have been described in patients with CRS that predispose to increased sinus mucosal bacterial colonization/
infection, including deficient local production of antimicrobial
lactoferrin and deficient functioning of the bitter taste receptor TAS2R38. Conversely, certain innate factors, namely IL-25,
IL-33, and
thymic stromal lymphopoietin (TSLP), are elaborated by sinus epithelial cells in response to microbial stimulation or airway injury and promote local TH2
inflammation. The precise physiologic role of these factors in innate or adaptive immunity is unclear, although
IL-33 might function as an
alarmin triggered by damage-associated molecular patterns. The
cytokines IL-25 and TSLP, similarly promote proinflammatory tissue responses. Another feature of epithelial dysregulation in patients with CRS is overproduction of eosinophil-promoting
C-C chemokines by sinus epithelium, perhaps driven in part through innate stimuli, as well as TH2
cytokines, such as
IL-13. Strategies to reduce the microbial stimulation of maladaptive TH2
inflammation or to suppress the local elaboration of TH2-promoting epithelial factors, such as
IL-33, have potential therapeutic benefit in patients with CRS, although the extent to which this is realized in patient care remains limited at present. This rostrum will summarize my views on the major microbial drivers of mucosal
inflammation and dysregulation of innate TH2-promoting factors in patients with CRS based on recent experimental data.