title: Aging affects the responsiveness of rat peritoneal macrophages to GM-CSF and IL-4.
abstract: Macrophages undergo significant functional alterations during aging. The aim of the present study was to investigate changes of rat macrophage functions and response to M1/M2 polarization signals with age. Therefore, resident and thioglycollate-elicited peritoneal macrophages from young (3-month-old) and aged (18-19-month-old) rats were tested for phagocytic capacity and ability to secrete inflammatory mediators following in vitro stimulation with LPS and GM-CSF, and IL-4, prototypic stimulators for classically (M1) and alternatively activated (M2) macrophages, respectively. Aging increased the frequency of monocyte-derived (CCR7+ CD68+) and the most mature (CD163+ CD68+) macrophages within resident and thioglycollate-elicited peritoneal macrophages, respectively. The ability to phagocyte zymosan of none of these two cell subsets was affected by either LPS and GM-CSF or IL-4. The upregulated production of IL-1β, IL-6 and IL-10 and downregulated that of TGF-β was observed in response to LPS in resident and thioglycollate-elicited macrophages from rats of both ages. GM-CSF elevated production of IL-1β and IL-6 in resident macrophages from aged rats and in thioglycollate-elicited macrophages from young rats. Unexpectedly, IL-4 augmented production of proinflammatory mediators, IL-1β and IL-6, in resident macrophages from aged rats. In both resident and thioglycollate-elicited macrophages aging decreased NO/urea ratio, whereas LPS but not GM-SCF, shifted this ratio toward NO in the macrophages from animals of both ages. Conversely, IL-4 reduced NO/urea ratio in resident and thioglycollate-elicited macrophages from young rats only. In conclusion, our study showed that aging diminished GM-CSF-triggered polarization of elicited macrophages and caused paradoxical IL-4-driven polarization of resident macrophages toward proinflammatory M1 phenotype. This age-related deregulation of macrophage inflammatory mediator secretion and phagocytosis in response to M1/M2 activators may lead to the deficient control of infectious and/or inflammatory diseases in advanced age.
authors.affiliation: Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, Belgrade, Serbia. miradim@sezampro.rs.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimitrijević
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera, "Torlak", Vojvode Stepe 458, Belgrade, 11152, Serbia.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stanojević
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera, "Torlak", Vojvode Stepe 458, Belgrade, 11152, Serbia.
authors.forename: Veljko
authors.initials: V
authors.lastname: Blagojević
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera, "Torlak", Vojvode Stepe 458, Belgrade, 11152, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Ćuruvija
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera, "Torlak", Vojvode Stepe 458, Belgrade, 11152, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vujnović
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera, "Torlak", Vojvode Stepe 458, Belgrade, 11152, Serbia.
authors.forename: Raisa
authors.initials: R
authors.lastname: Petrović
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, 11221, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Arsenović-Ranin
authors.affiliation: Institute of Chemistry in Medicine, School of Medicine, University of Belgrade, Višegradska 26, Belgrade, 11000, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Vujić
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, 11221, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Leposavić
mesh_terms: D000375:Aging; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D013864:Thioglycolates; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Aging; GM-CSF; IL-4; Macrophage polarization; Rat