Recombinant surfactant protein-D selectively increases apoptosis in eosinophils of allergic asthmatics and enhances uptake of apoptotic eosinophils by macrophages

Abstract

Pulmonary surfactant protein-D (SP-D) is a multifunctional, pattern recognition molecule involved in resistance to allergen challenge and pulmonary inflammation. In view of therapeutic effects of exogenous SP-D or recombinant fragment of human surfactant protein-D (rhSP-D) (composed of eight Gly-X-Y collagen repeat sequences, homotrimeric neck and lectin domains) in murine models of lung allergy and hypereosinophilic SP-D gene-deficient mice, we investigated the possibility of a direct interaction of purified rhSP-D with human eosinophils derived from allergic patients and healthy donors. rhSP-D showed a sugar- and calcium-dependent binding to human eosinophils, suggesting involvement of its carbohydrate recognition domain. While eosinophils from allergic patients showed a significant increase in apoptosis, oxidative burst and CD69 expression in presence of rhSP-D, eosinophils from healthy donors showed no significant change. However, these eosinophils from healthy donors when primed with IL-5 exhibited increase in apoptosis on incubation with rhSP-D. Apoptosis mediated by rhSP-D in primed eosinophils was not affected by the antioxidant, N-acetyl-L-cysteine. There was a manifold increase in binding of rhSP-D to apoptotic eosinophils than the normal eosinophils and rhSP-D induced a significant increase in uptake of apoptotic eosinophils by J774A.1 macrophage cells. The study suggests that rhSP-D mediated preferential increase of apoptosis of primed eosinophils while not affecting the normal eosinophils and increased phagocytosis of apoptotic eosinophils may be important mechanisms of rhSP-D and plausibly SP-D-mediated resolution of allergic eosinophilic inflammation in vivo.

Segmental Allergen Challenge Alters Multimeric Structure and Function of Surfactant Protein D in Humans

“…The multimeric form of SP-D binds to eosinophils in a saturable, calcium-and carbohydrate-dependent manner and increases apoptosis (32,36). However, there is an association between SP-D expression and eosinophilia (37) and SP-D-deficient mice display reduced symptoms in an Aspergillus-mediated model of asthma (38).…”

“…In the present study we also found that increased BAL eosinophilia was positively correlated with BAL SP-D level within challenged patients with asthma. Mechanistically, this may result from a loss of the ability of SP-D to bind to and promote apoptosis of eosinophils (36), because both the increase in eosinophil number and SP-D level was greatest in those patients whose SP-D had become oxidatively cross-linked. In this regard it is interesting to note that SNO-SP-D has a reduced ability to inhibit eotaxin-mediated eosinophil chemotaxis ( Figure 7).…”

Allergens/Antigens, Toxins and Polyketides of Important Aspergillus Species

“…Therapeutic potential of recombinant human surfactant protein D (rhSP-D) has been established by studies in murine models of lung allergy, hypereosinophilic SP-D gene-deficient mice and also with eosinophils from allergic patients. These studies clearly suggest therapeutic application of rhSP-D for allergic and invasive diseases [32][33][34][35][36][37]. Single nucleotide polymorphisms (SNPs); have been observed in these genes (SP-A, SP-D and MBL).…”

Les pneumoprotéines sériques, de nouveaux biomarqueurs pour phénotyper l’asthme du nourrisson ?

“…Cependant, l'action de SP-D sur les éosinophiles est dépendante de leur activation : il y a une sélectivité de SP-D pour les éosinophiles activés car ils ont moins de récepteurs inhibiteurs à leur surface, ce qui permet l'action de la protéine [32]. La sélectivité de SP-D vis-à-vis des éosinophiles activés a ainsi été démontrée chez l'homme, avec une corrélation entre l'augmentation du taux de protéine cationique des éosinophiles (ECP) dans le sputum et l'augmentation du taux de SP-D sérique après challenge allergénique dans une petite cohorte de patients adultes asthmatiques.…”