Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization.
The myeloid C-type lectin receptor Dectin-2 directs the generation of Th2 and Th17 immune responses to the house dust mite Dermatophagoides farinae through the generation of cysteinyl leukotrienes and proinflammatory cytokines, respectively, but a role for Dectin-2 in effector phase responses has not been described. In this study, we demonstrate that administration of the Dectin-2 mAb solely at the time of D. farinae challenge abrogated eosinophilic and neutrophilic inflammation in the bronchoalveolar lavage fluid and Th1, Th2, and Th17 inflammation in the lung of previously sensitized mice. Furthermore, Dectin-2 null mice (Clec4n(-/-)) sensitized with the adoptive transfer of D. farinae-pulsed wild-type (WT) bone marrow-derived dendritic cells (DCs) also had less D. farinae-elicited pulmonary inflammation, supporting an effector function for Dectin-2. The protection from pulmonary inflammation seen with the Dectin-2 mAb or in Clec4n(-/-) mice was associated with little or no reduction in lung-draining lymph node cells or their cytokine production and with no reduction in serum IgE. WT and Clec4n(-/-) mice recipients, sensitized with D. farinae-pulsed WT bone marrow-derived DCs, had comparable levels of D. farinae-elicited IL-6, IL-23, TNF-α, and cysteinyl leukotrienes in the lung. By contrast, D. farinae-elicited CCL4 and CCL8 production from pulmonary CD11c(+)CD11b(+)Ly6C(+) and CD11c(+)CD11b(+)Ly6C(-)CD64(+) monocyte-derived DCs was reduced in Clec4n(-/-) recipients. Addition of CCL8 at the time of D. farinae challenge abrogated the protection from eosinophilic, neutrophilic, and Th2 pulmonary inflammation seen in Clec4n(-/-) recipients. Taken together, these results reveal that Dectin-2 regulates monocyte-derived DC function in the pulmonary microenvironment at D. farinae challenge to promote the local inflammatory response.
Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115;
Matthew W
MW
Parsons
Li
L
Li
Aaron M
AM
Wallace
Min Jung
MJ
Lee
Howard R
HR
Katz
James M
JM
Fernandez
Shinobu
S
Saijo
Yoichiro
Y
Iwakura
K Frank
KF
Austen
Yoshihide
Y
Kanaoka
Nora A
NA
Barrett
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D039741:Antigens, Dermatophagoides / Q000276:immunology; D000950:Antigens, Ly / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D054407:Chemokine CCL4 / Q000096:biosynthesis / Q000378:metabolism; D054412:Chemokine CCL8 / Q000096:biosynthesis / Q000378:metabolism; D003545:Cysteine / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D040001:Dermatophagoides farinae / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015289:Leukotrienes / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*; D017452:Receptors, IgG / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D039741:Antigens, Dermatophagoides; D000950:Antigens, Ly; D039481:CD11b Antigen; D039521:CD11c Antigen; C515454:Ccl8 protein, mouse; D054407:Chemokine CCL4; D054412:Chemokine CCL8; D053759:Interleukin-23; D015850:Interleukin-6; D037181:Lectins, C-Type; D015289:Leukotrienes; C494192:Ly-6C antigen, mouse; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; C445340:dectin-2, mouse; D007073:Immunoglobulin E; D003545:Cysteine