Chemokine Receptor CCR2 but Not CCR5 or CCR6 Mediates the Increase in Pulmonary Dendritic Cells during Allergic Airway Inflammation

Abstract

Increased numbers of pulmonary dendritic cells (DCs) are recruited to the lungs during allergic airway inflammation and contribute to the maintenance of the inflammatory immune response. The chemokine receptors that directly control DC accumulation into the lungs are largely unknown. To explore this issue, we generated mixed bone marrow chimeric mice containing both wild-type and knockout cells for a given chemokine receptor. After induction of allergic airway inflammation, we specifically tracked and compared chemokine receptor knockout vs wild-type DC populations through various lung compartments. Using this approach, we show that CCR2, but not CCR5 or CCR6, directly controls the accumulation of DCs into allergic lungs. Furthermore, the size of inflammatory monocyte populations in peripheral blood was strikingly CCR2 dependent, suggesting that CCR2 primarily mediates the release of monocytic DC precursors into the bloodstream.

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

“…Induction of CCR7 on human mDCs by UPM, as we report, supports the results from murine experiments that diesel exhaust particle‐laden DCs translocate to lymph nodes after diesel exhaust particle instillation in to the lungs,31 and is important given that lymph nodes are the primary site for priming of new immune responses in vivo . Decreased expression of CCR2 and CCR6 on mDCs after exposure to UPM in the lungs as indicated by our results may act to release these mDCs from the pulmonary environment, as both are important in chemotaxis of inflammatory DCs in to the lungs 32, 33, 34. However, the resulting effects of down‐regulation of CCR2 and CCR6 on DCs are probably more complex – for example Sato and colleagues have previously shown CCR2 to have a role in migration of Langerhans cells (skin‐resident dendritic cells) to and within lymph nodes, and CCR2 −/− knockout mice to have an exaggerated T helper type 2 immune response to Leishmania major infection 35…”

Origin and functional specializations of DC subsets in the lung

“…The recruited inflammatory CD11b 1 DC form part of the inflammatory response to allergens and are derived from monocytes. These CD11b 1 DC rely on CCR2, not CCR5 or CCR6, to accumulate in the lung [58]. Depletion of these DC at the time of lung allergen challenge reduces the salient features of asthma, such as airway eosinophilia, metaplasia of goblet cells and bronchial hyperreactivity [4,24].…”

Signal Relay by CC Chemokine Receptor 2 (CCR2) and Formylpeptide Receptor 2 (Fpr2) in the Recruitment of Monocyte-derived Dendritic Cells in Allergic Airway Inflammation

“…In mice, Ly6C high conventional monocytes are CX3CR1 low , CCR2 high monocytes differentiate into inflammatory DCs and acquire the capacity to prime T cellmediated immune responses (5). In the lung, inflammatory stimuli such pathogen-derived TLR ligands or exposure to environmental pollutants trigger the production of chemokines that recruit monocyte-derived inflammatory DCs in a CCR2-dependent manner (2,3,6,7), presumably via interaction with the ligand CCL2. However, other chemokine receptors have also been implicated in the recruitment of monocyte-derived inflammatory DCs into the lung as evidenced by observations with CCR5 and CCR6 knock-out mice in cigarette smoke inhalation models (8,9).…”