title: A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness of bone-marrow-derived macrophages to Toll-like receptor agonists.
abstract: Macrophages play a pivotal role in innate and acquired immune responses to Schistosoma mansoni. Classical (M1) or alternative (M2) activation states of these cells further delineate their roles in tissue damage through innate immunity or fibrotic remodeling, respectively. In the present study, we addressed the following question: Does systemic Th2-type cytokine polarization evoked by S. mansoni affect macrophage differentiation and activation? To this end, we analyzed bone marrow-derived macrophages from mice with S. mansoni egg-induced pulmonary granulomas and unchallenged (or naïve) mice to determine their activation state and their response to specific TLR agonists, including S. mansoni egg antigens. Unlike naïve macrophages, macrophages from Th2-polarized mice constitutively expressed significantly higher "found in inflammatory zone-1" (FIZZ1) and ST2 (M2 markers) and significantly lower NO synthase 2, CCL3, MIP-2, TNF-alpha, and IL-12 (M1 markers). Also, compared with naïve macrophages, Th2-polarized macrophages exhibited enhanced responses to the presence of specific TLR agonists, which consistently induced significantly higher levels of gene and protein levels for M2 and M1 markers in these cells. Together, these data show that signals received by bone marrow precursors during S. mansoni egg-induced granuloma responses dynamically alter the development of macrophages and enhance the TLR responsiveness of these cells, which may ultimately have a significant effect on the pulmonary granulomatous response.
authors.affiliation: Department of Pathology, University of Michigan Medical School, 4057 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-0602, USA.
authors.forename: Amrita D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Tracy
authors.initials: T
authors.lastname: Raymond
authors.forename: Ana L
authors.initials: AL
authors.lastname: Coelho
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000818:Animals; D054414:Chemokine CCL17 / Q000494:pharmacology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D018899:CpG Islands; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015769:Granuloma, Respiratory Tract / Q000209:etiology / Q000276:immunology*; D016753:Interleukin-10 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D008171:Lung Diseases / Q000209:etiology / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D010063:Ovum / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D051193:Toll-Like Receptors; D016753:Interleukin-10; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine; D011070:Poly I-C