A CCL24-dependent pathway augments eosinophilic airway inflammation in house dust mite-challenged Cd163−/− mice

Abstract

CD163 is a macrophage scavenger receptor with anti-inflammatory and pro-inflammatory functions. Here, we report that alveolar macrophages (AMΦs) from asthmatic subjects had reduced cell surface expression of CD163, which suggested that CD163 might modulate the pathogenesis of asthma. Consistent with this, house dust mite (HDM)-challenged Cd163−/− mice displayed increases in airway eosinophils and mucous cell metaplasia (MCM). The increased airway eosinophils and MCM in HDM-challenged Cd163−/− mice were mediated by augmented CCL24 production and could be reversed by administration of a neutralizing anti-CCL24 antibody. A proteomic analysis identified the calcium-dependent binding of CD163 to Dermatophagoides ptyeronyssinus peptidase 1 (Der p1). Der p1-challenged Cd163−/− mice had the same phenotype as HDM-challenged Cd163−/− mice with increases in airway eosinophils, MCM and CCL24 production, while Der p1 induced CCL24 secretion by bone marrow-derived macrophages (BMMΦs) from Cd163−/− mice, but not BMMΦs from WT mice. Lastly, airway eosinophils and bronchoalveolar lavage fluid CCL24 levels were increased in Der p1-challenged WT mice that received adoptively transferred AMΦ’s from Cd163−/− mice. Thus, we have identified CD163 as a macrophage receptor that binds Der p1. Furthermore, we have shown that HDM-challenged Cd163−/− mice have increased eosinophilic airway inflammation and MCM that are mediated by a CCL24-dependent mechanism.

Macrophage-specific nanotechnology-driven CD163 overexpression in human macrophages results in an M2 phenotype under inflammatory conditions

“…Similarly, the crosslink of CD163 with some antibodies triggers pro-inflammatory immune responses (Ritter, et al, 2001). On the other hand, CD163 seems to bind to dust mites (Dai, et al, 2016) and cockroach allergens (Mushaben, 2015), which protects the host from inflammatory reactions. Together, these data show that the conditions or stimuli present in a system can determine the immunomodulatory actions of CD163, which are not limited to the Hb-Hp complex interaction.…”

Systemic corticosteroid therapy augments ex vivo release of sCD163 by peripheral blood monocytes of asthmatic patients

“…A reduced expression of CD163 on broncho-alveolar macrophages in patients with asthma suggests that its antiinflammatory role in regulation of inflammatory responses in the lung of asthmatic patients may be impaired [25]. However, the reverse association of the serum sCD163 level with FEV 1 in patients in asthma was observed [25]. This implicates that increased CD163 shedding already within circulation is associated with the loss of lung function.…”

“…A local expression of CD163 in the lungs during respiratory infection implies its role as an pulmonary defence element [24]. A reduced expression of CD163 on broncho-alveolar macrophages in patients with asthma suggests that its antiinflammatory role in regulation of inflammatory responses in the lung of asthmatic patients may be impaired [25]. However, the reverse association of the serum sCD163 level with FEV 1 in patients in asthma was observed [25].…”

“…This implicates that increased CD163 shedding already within circulation is associated with the loss of lung function. A mouse model of allergic asthma provided further evidence for an important role of CD163 in regulation of inflammatory response in the airways [25]. Genetically modified mice, which do not express CD163, were characterized by a greater airway inflammation in response to a house dust mite allergen challenge [26].…”

Generation of murine macrophage-derived cell lines expressing porcine CD163 that support porcine reproductive and respiratory syndrome virus infection

“…As a type I membrane protein, the extracellular region of CD163 contains nine scavenger receptor cysteine-rich (SRCR) domains (SRCR1-9) and is anchored by a single transmembrane portion and a short cytoplasmic domain [ 42 , 43 ]. Biologically, membrane-associated CD163 is responsible for mediating endocytosis of hemoglobin-haptoglobin complexes to prevent tissue damage caused by free hemoglobin-catalyzed production of iron-derived hydroxyl radicals [ 44 – 46 ] and modulating systemic immune homeostasis, particularly with respect to anti-inflammation [ 47 ]. In in vivo study, alveolar macrophages from asthmatic patients with reduced cell-surface expression of CD163 associated with inflammatory effects, which was similar as that observed in CD163 knock-out mice [ 47 ].…”