MicroRNA-Mediated Calcineurin Signaling Activation Induces CCL2, CCL3, CCL5, IL8 and Chemotactic Activities in 4,4’-Methylene Diphenyl Diisocyanate Exposed Macrophages

Occupational exposure to 4,4’-methylene diphenyl diisocyanate (MDI), the most widely used monomeric diisocyanate, is one of the leading causes of occupational asthma (OA). Pathophysiological mechanism(s) by which how MDI causes OA is still warranted to be elucidated. Alveolar macrophages are the most abundant immune cell type in the lung, and these cells serve as one of the first immune responders against inhaled pathogens, particles, stimuli, and chemical allergens such as dNCOs. Upon encountering outside stimuli, alveolar macrophages react by phagocytosis as well as producing and secreting different mediators such as cytokines, chemokines, and others, into the alveoli microenvironment to orchestrate the initiation of inflammatory/immune responses. Dysfunction of alveolar macrophages, including elevated production and secretion of pro-inflammatory cytokines and other immune mediators, has been shown to play an important role in asthma pathogenesis. In the clinical setting, the levels of many immune mediators produced by macrophages have been found elevated in the asthmatic airway. However, both the levels of these asthma-associated, macrophage-secreted inflammatory/immune mediators in MDI-OA patients’ airways and how expression of these mediators change in response to MDI exposure in alveolar macrophages are largely undetermined. Previously, we demonstrated a microRNA (miR)-206-3p and miR-381-3p mediated PPP3CA/Calcineurin signaling induced inducible nitric oxide synthase (iNOS) transcription in macrophages and bronchoalveolar lavage cells (BALCs) after acute MDI exposure; however, whether this mechanism participates in regulation of other asthma-associated mediators secreted by macrophages/BALCs after MDI exposure is currently unknown. The first aim of this study was to identify candidate asthma-associated, macrophage-secreted mediators that can be regulated after MDI exposure. After identified the candidate mediators can be regulated by MDI-exposure, we investigated the roles of miR-mediated calcineurin signaling in regulation of these candidate mediators' expressions in relation to the exposure to MDI.