Abstract
Proliferation of dendritic cell (DC)—restricted progenitor cells in bone marrow compartment is tightly regulated at steady state and responds to multiple tissue-specific triggers during disturbed homeostasis such as obesity. DCs in the lung stem from a rapidly dividing DC-restricted progenitor cells and are effective at generating adaptive immune responses in allergic airway inflammation. Precisely, how DC-restricted progenitor expansion and differentiation are influenced by airway inflammation to maintain constant supply of myeloid DCs is poorly understood. Here we show that a high fat diet (HFD) induces oxidative stress and accelerates the expansion of DC- restricted progenitor cells in bone marrow and correlates with persistent induction of p38 mitogen activated protein kinase (MAPK), which is blocked with a selective p38α/β MAPK inhibitor. Mice fed a HFD and sensitized to inhaled allergen house dust mite (HDM) led to alterations of DC- restricted progenitor cells that were characterized by increased expansion and seeding of lung DCs in airway inflammation. Mechanistically, we establish that the expansion induced by HFD dysregulates the expression of a disintegrin and metallopeptidase domain 17 (Adam17) and is required for p38 MAPK activation in DC-restricted progenitors. These results demonstrates that obesity produces persistent changes in DC precursors and that elevation of Adam17 expression is tightly coupled to p38 MAPK and is a key driver of proliferation. Altogether, these data provide phenotypic and mechanistic insight into dendritic cell supply chain in obesity-associated airway inflammation.
Highlights
The prevalence of obesity continues to rise at a staggering rate in developed countries and is considered to be a proven risk-factor for both allergic and non-allergic asthma [1,2,3]
Our results demonstrate that obesity has a regulatory effect on lineage-specific dendriticcell progenitors in the bone marrow (BM) compartment
DCrestricted common DC progenitors (CDPs) population display a limited perturbation at steady-state, they show an exacerbated proliferative response and expansion in obesity along with quantitative increase of lung myeloid cells in airway inflammation
Summary
The prevalence of obesity continues to rise at a staggering rate in developed countries and is considered to be a proven risk-factor for both allergic and non-allergic asthma [1,2,3]. Dietary high fat is one of the key factor to the development of obesity in humans. A HFD qualitatively or quantitatively modifies lung adaptive immune response and airway inflammation by sensitization to inhaled allergen [8, 9]. HFD affects both the numbers and physiological function of lung immune cells stem from myeloid and lymphoid precursors in the BM [18, 19]. To meet the enhanced demand of these cells the BM-lung axis are salient in controlling allergic airway inflammation [20]
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