Role of C-C Motif Ligand 2 and C-C Motif Receptor 2 in Murine Pulmonary Graft-versus-Host Disease after Lipopolysaccharide Inhalations
Autor: | Julia L. Nugent, Scott M. Palmer, W. Michael Foster, Margaret E. Nelson, Christine V. Kinnier, Kymberly M. Gowdy, Francine L. Kelly, Matthew A. Lyes, Jesse Sun, Michael D. Gunn, Tereza Martinu |
---|---|
Rok vydání: | 2014 |
Předmět: |
Lipopolysaccharides
Male Pulmonary and Respiratory Medicine CCR2 Chemokine Lipopolysaccharide Receptors CCR2 T-Lymphocytes Clinical Biochemistry Graft vs Host Disease CCL2 chemistry.chemical_compound medicine Animals Receptor Lung Molecular Biology Interleukin 5 Cells Cultured Chemokine CCL2 Original Research biology Hematopoietic Stem Cell Transplantation Cell Differentiation Dendritic Cells Cell Biology Hematopoietic Stem Cells medicine.disease Coculture Techniques Mice Inbred C57BL Haematopoiesis Graft-versus-host disease chemistry Immunology biology.protein Interleukin-5 |
Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 51:810-821 |
ISSN: | 1535-4989 1044-1549 |
DOI: | 10.1165/rcmb.2013-0451oc |
Popis: | Environmental exposures are a potential trigger of chronic pulmonary graft-versus-host disease (pGVHD) after successful recovery from hematopoietic cell transplant (HCT). We hypothesized that inhalations of LPS, a prototypic environmental stimulus, trigger pGVHD via increased pulmonary recruitment of donor-derived antigen-presenting cells (APCs) through the C-C motif ligand 2 (CCL2)-C-C motif receptor 2 (CCR2) chemokine axis. B10.BR(H2(k)) and C57BL/6(H2(b)) mice underwent allogeneic (Allo) or syngeneic (Syn) HCT with wild-type (WT) C57BL/6, CCL2(-/-), or CCR2(-/-) donors. After 4 weeks, recipient mice received daily inhaled LPS for 5 days and were killed at multiple time points. Allo mice exposed to repeated inhaled LPS developed prominent lymphocytic bronchiolitis, similar to human pGVHD. The increase in pulmonary T cells in Allo mice after LPS exposures was accompanied by increased CCL2, CCR2, and Type-1 T-helper cytokines as well as by monocytes and monocyte-derived dendritic cells (moDCs) compared with Syn and nontransplanted controls. Using CCL2(-/-) donors leads to a significant decrease in lung DCs but to only mildly reduced CD4 T cells. Using CCR2(-/-) donors significantly reduces lung DCs and moDCs but does not change T cells. CCL2 or CCR2 deficiency does not alter pGVHD pathology but increases airway hyperreactivity and IL-5 or IL-13 cytokines. Our results show that hematopoietic donor-derived CCL2 and CCR2 regulate recruitment of APCs to the Allo lung after LPS exposure. Although they do not alter pathologic pGVHD, their absence is associated with increased airway hyperreactivity and IL-5 and IL-13 cytokines. These results suggest that the APC changes that result from CCL2-CCR2 blockade may have unexpected effects on T cell differentiation and physiologic outcomes in HCT. |
Databáze: | OpenAIRE |
Externí odkaz: |