Lung CD200 Receptor Activation Abrogates Airway Hyperresponsiveness in Experimental Asthma

Abstract

In allergic asthma, homeostatic pathways are dysregulated, which leads to an immune response toward normally innocuous antigens. The CD200-CD200 receptor pathway is a central regulator of inflammation, and CD200 expression was recently found to be down-regulated in circulating leukocytes of patients with asthma. Given the antiinflammatory properties of CD200, we investigated whether local delivery of recombinant CD200 (rCD200) could reinstate lung homeostasis in an experimental model of asthma. Brown Norway rats were sensitized with ovalbumin (OVA) and alum. rCD200 was intratracheally administered 24 hours before OVA challenge, and airway responsiveness to methacholine was measured 24 hours after the allergen challenge. Inflammation was also assessed by measuring cell recruitment and cytokine levels in bronchoalveolar lavages, as well as lung and draining lymph node accumulation of dendritic cells (DCs) and T cells. In sensitized rats, rCD200 abolished airway hyperresponsiveness, whereas the sham treatment had no effect. In addition, rCD200 strongly reduced OVA-induced lung accumulation of myeloid DCs, CD4(+) T cells, and T helper type 2 cells. This was associated with a strong reduction of OVA-induced IL-13 level and with an increase of IL-10 in supernatants of bronchoalveolar lavages. Lung eosinophilia and draining lymph node accumulation of myeloid DCs and T cells were not affected by rCD200. Overall, these data reveal that rCD200 can inhibit airway hyperresponsiveness in a model of asthma by a multistep mechanism associated with local alterations of the T cell response and the cytokine milieu.

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects ofβ2-Adrenoceptor Agonists

“…DUSP1 is a phosphatase that catalyzes the inactivation of the three core MAP kinases: extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun-N-terminal kinase (Liu et al, 2007), which are central regulators of virtually all aspects of inflammatory processes, including gene expression (Kyriakis and Avruch, 2012). SOCS3 negatively regulates IL-6-, IL-12-, and G-CSFsignaling by inhibiting the JAK/STAT pathway (Yoshimura et al, 2007), whereas CD200 interacts with CD200R-bearing cells, such as macrophages, to suppress proinflammatory cytokine generation (Snelgrove et al, 2008); it may also attenuate airway hyperresponsiveness (Lauzon-Joset et al, 2015).…”

Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update

“…CD200 is a transmembrane glycoprotein expressed on haematopoietic and non‐haematopoietic cells, which by binding its cognate receptor, CD200R, on alveolar macrophages, down‐regulates cytokine production (Snelgrove et al , ). This interaction also suppresses AHR in a murine model of allergic asthma (Vaine and Soberman, ; Lauzon‐Joset et al , ). Similarly, the secreted protein, CRISPLD2, attenuates gene toll‐like receptor‐4‐mediated, pro‐inflammatory signalling by binding and inactivating lipopolysaccharide/lipid A (Wang et al , ; Himes et al , ; Vasarhelyi et al , ).…”

Cross-Talk Between Alveolar Macrophages and Lung Epithelial Cells is Essential to Maintain Lung Homeostasis

“…In steady-state lung, AMs are in an immunosuppressed state and their phenotype is tightly control by the lung microenvironment. They express high level of CD200 receptor (CD200R) which is associated with M2 phenotype ( 42 , 43 ) and are involved in the downregulation of immune inflammation ( 44 , 45 ). This may be important for tolerating innocuous inhaled agent.…”