title: Downregulation of key early events in the mobilization of antigen-bearing dendritic cells by leukocyte immunoglobulin-like Receptor B4 in a mouse model of allergic pulmonary inflammation.
abstract: Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) null mice have an exacerbated T helper cell type 2 (Th2) immune response and pulmonary inflammation compared with Lilrb4(+/+) animals when sensitized intranasally with ovalbumin (OVA) and low-dose lipopolysaccharide (LPS) followed by challenge with OVA. Moreover, OVA-challenged Lilrb4(-/-) mice exhibit greater migration of antigen (Ag)-bearing dendritic cells (DCs) to lymph nodes and accumulation of interleukin 4- and interleukin 5-producing lymph node lymphocytes. The main objective of this study was to determine how the absence of LILRB4 leads to a greater number of DCs in the lymph nodes of Ag-challenged mice and increased lung Th2 inflammation. Mice were sensitized intranasally with PBS alone or containing OVA and LPS; additional cohorts were subsequently challenged with OVA. Expression of chemokine (C-C motif) ligand 21 (CCL21) in the lung was assessed immunohistologically. OVA ingestion and expression of LILRB4 and chemokine (C-C motif) receptor 7 (CCR7) were quantified by flow cytometry. Inhalation of OVA and LPS induced upregulation of LILRB4 selectively on lung Ag-bearing DCs. After sensitization and challenge, the lung lymphatic vessels of Lilrb4(-/-) mice expressed more CCL21, a chemokine that directs the migration of DCs from peripheral tissue to draining lymph nodes, compared with Lilrb4(+/+) mice. In addition, lung DCs of challenged Lilrb4(-/-) mice expressed more CCR7, the CCL21 receptor. The lungs of challenged Lilrb4(-/-) mice also contained significantly greater numbers of CD4+ cells expressing interleukin-4 or interleukin-5, consistent with the greater number of Ag-bearing DCs and Th2 cells in lymph nodes and the attendant exacerbated Th2 lung pathology. Our data establish a new mechanism by which LILRB4 can downregulate the development of pathologic allergic inflammation: reduced upregulation of key molecules needed for DC migration leading to decreases in Th2 cells in lymph nodes and their target tissue.
authors: Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Laura B
authors: LB
authors: Fanning
authors: Carolyn C
authors: CC
authors: Buckley
authors: Wei
authors: W
authors: Xing
authors: Rebecca G
authors: RG
authors: Breslow
authors: Howard R
authors: HR
authors: Katz
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D054421:Chemokine CCL21 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D015848:Interleukin-5; C489448:Lilrb4 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D011971:Receptors, Immunologic; D015847:Interleukin-4; D010047:Ovalbumin