Dimethyl fumarate attenuates T helper type 2 (Th2) -mediated allergic airway inflammation by modulating dendritic cell function

Abstract

Abstract Dendritic cells (DCs) are primary antigen presenting cells in lungs that promote Th2 cell mediated immunity to house dust mite (HDM) allergen. DCs are attractive therapeutic targets to modulate allergen-induced airway inflammation and adaptive immune responses. Dimethyl fumarate (DMF) are methyl esters of fumaric acid and regulates immune cell differentiation and effector functions. However, the effect of DMF on lung DCs has not yet been addressed. Here, we investigated the effect of DMF treatment employing murine model of HDM-induced experimental allergic asthma and DC adoptive transfer experiment. We show that local DMF application attenuates airway inflammation, mucous cell hyperplasia, and airway resistance to increasing dosage of inhaled methacholine. Notably, DMF administration in the allergen challenge phase significantly inhibited the lung recruitment of CD11b+ conventional DCs (cDC2) and suppressed Th2 cytokine producing IL4, IL5, and IL13 CD4+ T cells. In lung draining mediastinal lymph node (mLNs), DMF treatment significantly induces CD4+T regulatory (Tregs) cells. Moreover, prior to administration of fluorescent-labeled HDM, single DMF application to naïve mice impeded the migration of CD11b+ cDC2 to the draining mLNs. Adoptive transfer of DMF treated CD11c+ HDM-pulsed DCs to naïve mice with subsequent intranasal HDM-challenge similarly attenuates the features of airway inflammation. Collectively, our findings suggest that local DMF application modulates lung DCs function, thereby attenuates airway inflammation and is a potent antiasthmatic therapeutic agent.