The antimicrobial/elastase inhibitor elafin regulates lung dendritic cells and adaptive immunity.
Infections with bacteria and viruses such as adenovirus are a feature of chronic lung diseases such as chronic obstructive pulmonary diseases (COPD), and may be instrumental in the generation of disease exacerbations. We have previously shown in acute models that elafin (a lung natural chemotactic molecule for macrophages and neutrophils, with potent antimicrobial and neutrophil elastase inhibitor activity) is upregulated in infection and modulates innate immunity. Here we present data using two independent systems of elafin overexpression in vivo (recombinant adenovirus [Ad-elafin] and an elafin transgenic mouse line) to examine the function of elafin in adaptive immunity. We show that elafin increases the number (immunofluorescence) and activation status (flow cytometric measurement) of CD11c+/MHCII+ lung dendritic cells in vivo. Analysis of cytokines produced by spleen and lung cells, and of antibodies measured in serum and bronchoalveolar lavage fluid, shows that the immunity induced is biased toward a type 1 response (production of IL-12, IFN-gamma, and IgG2a). Furthermore, elafin overexpression protected mice against further challenge with Ad-LacZ, as assessed by antibody levels and neutralization titer, as well as LacZ expression in lung tissue. Thus, the pleiotropic molecule elafin has significant potential in modulating antigen-presenting cell numbers and activity, and could be beneficial in mucosal protective strategies.
Roghanian
Ali
A
MRC Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh University, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
Williams
Steven E
SE
Sheldrake
Tara A
TA
Brown
Tom I
TI
Oberheim
Karen
K
Xing
Zhou
Z
Howie
Sarah E M
SE
Sallenave
Jean-Michel
JM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D007109:Immunity / Q000276:immunology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology; D009500:Neutralization Tests; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D014611:Vaccination; D019444:Vaccines, DNA
D000914:Antibodies, Viral; D039521:CD11c Antigen; D016207:Cytokines; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D019444:Vaccines, DNA; D019272:Leukocyte Elastase