4,4’-Methylene Diphenyl Diisocyanate Exposure Induces Expression of Alternatively Activated Macrophage-Associated Markers and Chemokines Partially Through Krüppel-Like Factor 4 Mediated Signaling in Macrophages

Exposure to 4,4’-methylene diphenyl diisocyanate (MDI), the most widely used monomeric diisocyanate, in the occupational setting may lead to the development of occupational asthma (OA). Currently, the underlying molecular mechanism(s) by which MDI induces OA remain an active area of research. Alveolar macrophage dysfunctions play important roles in asthma pathogenesis. Upon exposure to outside stimuli, macrophages are polarized into either classically activated (M1) or alternatively activated (M2) phenotypes. Macrophage polarization is associated with asthma development where M2 macrophage populations are usually pronounced in lungs of asthmatic patients. Recent in vivo studies demonstrated that M2 macrophage associated markers and chemokines were induced by MDI exposure, indicating that MDI may induce M2 macrophage polarization; however, the underling molecular mechanism(s) by which MDI causes induction of M2 associated markers and chemokines is unclear. M2 macrophage polarization can be regulated by activation of several M2 associated transcription factors; however, whether MDI exposure regulates these transcription factors is unknown. We hypothesize that MDI exposure induces M2 macrophage associate markers and chemokines through upregulation of M2 macrophage-associated transcription factors in macrophages. The first aim of this study is to verify whether MDI-exposure can induce M2 macrophage-associated markers and chemokine expression that were observed in previous studies and to identify candidate M2 macrophage-associated transcription factors in response to MDI exposure that may account for the M2 macrophage polarization. After identification of the candidate transcription factor(s) that can be regulated by MDI-exposure, we investigate the roles of the candidate transcription factor in regulation of these candidate M2 macrophage associate markers and chemokines in relation to the exposure to MDI.