Toll-like receptor 4 and Syk kinase shape dendritic cell-induced immune activation to major house dust mite allergens

Frontiers in Medicine

Medicine

Jaap H. Akkerdaas¹  Stefanie Busold¹  Esther M. Zijlstra-Willems¹  Esther C. de Jong¹  Teunis B. H. Geijtenbeek¹  Sander W. Tas²  Ronald van Ree³  Kees van der Graaf⁴ 

[1] Amsterdam University Medical Centers, location AMC, Department of Experimental Immunology, Amsterdam, Netherlands;Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, Netherlands;Amsterdam University Medical Centers, location AMC, Department of Experimental Immunology, Amsterdam, Netherlands;Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, Netherlands;Amsterdam Rheumatology and Immunology Center, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands;Amsterdam University Medical Centers, location AMC, Department of Experimental Immunology, Amsterdam, Netherlands;Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, Netherlands;Amsterdam University Medical Centers, location AMC, Department of Otorhinolaryngology, Amsterdam, Netherlands;Citeq Biologics, Groningen, Netherlands;

关键词: house dust mite allergy;    Der p 1;    Der p 2;    TLR4;    Syk;    dendritic cell activation;   

DOI  :  10.3389/fmed.2023.1105538

 received in 2022-11-22, accepted in 2023-07-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundHouse dust mite (HDM) is a major cause of respiratory allergic diseases. Dendritic cells (DCs) play a central role in orchestrating adaptive allergic immune responses. However, it remains unclear how DCs become activated by HDM. Biochemical functions of the major HDM allergens Der p 1 (cysteine protease) and Der p 2 (MD2-mimick) have been implicated to contribute to DC activation.MethodsWe investigated the immune activating potential of HDM extract and its major allergens Der p 1 and Der p 2 using monocyte-derived DCs (moDCs). Maturation and activation markers were monitored by flow cytometry and cytokine production by ELISA. Allergen depletion and proteinase K digestion were used to investigate the involvement of proteins, and in particular of the major allergens. Inhibitors of spleen tyrosine kinase (Syk), Toll-like receptor 4 (TLR4) and of C-type lectin receptors (CLRs) were used to identify the involved receptors. The contribution of endotoxins in moDC activation was assessed by their removal from HDM extract.ResultsHDM extract induced DC maturation and cytokine responses in contrast to the natural purified major allergens Der p 1 and Der p 2. Proteinase K digestion and removal of Der p 1 or Der p 2 did not alter the immune stimulatory capacity of HDM extract. Antibodies against the CLRs Dectin-1, Dectin-2, and DC-SIGN did not affect cytokine responses. In contrast, Syk inhibition partially reduced IL-6, IL-12 and completely blocked IL-10. Blocking TLR4 signaling reduced the HDM-induced IL-10 and IL-12p70 induction, but not IL-6, while endotoxin removal potently abolished the induced cytokine response.ConclusionOur data strongly suggest that HDM-induced DC activation is neither dependent on Der p 1 nor Der p 2, but depend on Syk and TLR4 activation, which might suggest a crosstalk between Syk and TLR4 pathways. Our data highlight that endotoxins play a potent role in immune responses targeting HDM.

【 授权许可】

Unknown   
Copyright © 2023 Busold, Akkerdaas, Zijlstra-Willems, van der Graaf, Tas, de Jong, van Ree and Geijtenbeek.