Ineffective elimination of Leishmania major by inflammatory (MRP14-positive) subtype of monocytic cells.
Myeloid-related protein (MRP) 14, an intracellular protein involved in calcium-dependent activation of myeloid cells, presents a differentiation marker for a subtype of macrophages. In experimental leishmaniasis, BALB/c mice succumb to visceral dissemination after infection with L. major, due to a Th2 cell response, while C57Bl/6 mice develop protective immunity associated with a Th1 cell response. We have previously shown that resistance in (C57Bl/6 mice was also associated with a significantly lower percentage of MRP14-positive cells in the infiltrate than in susceptible BALB/c mice. In C57Bl/6 mice, weekly injections of bone marrow (BM) cells enriched with MRP14-positive cells (d1 of culture) did not reverse, but prolonged the course of infection, associated with increased local parasite spread. In BALB/c mice a single dose of an antiphlogistic agent (dexamethasone or lipoxygenase inhibitor) was associated with reduction of infiltrating MRP14-positive cells and also with a decrease of parasite loads in footpads, lymph nodes as well as spleens, and with delayed progression of disease, Double labeling experiments in vitro revealed that at least 43.1% of MRP14-positive mononuclear cells in BM cultures (8h) had phagocytosed parasites after 4 h of co-incubation. Activation by IFN-gamma (20 U/ml) for 24h and 48h did not significantly reduce parasite load in these cells. In contrast, 77.0% of F4/80-positive macrophages (6d of culture) were infected with L. major parasites and these cells responded to activation with IFN-gamma (20 U/ml) with significant reduction of parasite load (25.3%). The protein MRP14 did not have an effect on parasite survival in vitro. Thus, the impaired capability of MRP14-positive cells to kill L. major upon stimulation may be one reason for the adverse course of infection observed with their increased appearance.
Steinbrink
K
K
Institute of Experimental Dermatology, University of Münster, Germany.
Schönlau
F
F
Rescher
U
U
Henseleit
U
U
Vogel
T
T
Sorg
C
C
Sunderkötter
C
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000943:Antigens, Differentiation / Q000032:analysis* / Q000494:pharmacology; D040502:Calgranulin B; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D018320:Leishmania major / Q000187:drug effects / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology; D008198:Lymph Nodes / Q000469:parasitology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000276:immunology*; D010587:Phagocytosis; D011804:Quinolines / Q000008:administration & dosage; D009418:S100 Proteins / Q000032:analysis* / Q000494:pharmacology; D013154:Spleen / Q000469:parasitology
D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D040502:Calgranulin B; D011804:Quinolines; D009418:S100 Proteins; C036763:monocyte-macrophage differentiation antigen; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D003907:Dexamethasone; D007371:Interferon-gamma