BACKGROUND: Within the last decade, macrophages have been shown to be capable of differentiating toward a classically activated phenotype (M1) with a high antimicrobial potential or an alternatively activated phenotype (M2). Some pathogens are capable of interfering with differentiation in order to down-regulate the anti-microbial activity and enhance their survival in the host. RESULTS: To test this ability in Salmonella enterica serovar Typhimurium, we infected porcine alveolar macrophages with wild-type Salmonella Typhimurium and its isogenic mutants devoid of two major pathogenicity islands, SPI-1 and SPI-2. The induction of genes linked with M1 or M2 polarization was determined by quantification of gene expression by RT-qPCR. The ΔSPI-1 mutant induced a high, dose-dependent M1 response but a low M2 response in infected macrophages. On the other hand, wild-type Salmonella Typhimurium induced a low M1 response but a high, dose-dependent M2 response in infected macrophages. The response to ΔSPI-2 mutant infection was virtually the same as the wild-type strain. CONCLUSIONS: We therefore propose that Salmonella Typhimurium DT104 studied here can polarize macrophages towards the less bactericidal M2 phenotype and that this polarization is dependent on the type III secretion system encoded by SPI-1.

Veterinary Research Institute Hudcova Brno Czech Republic

Zobrazit více v PubMed

Ginocchio CC, Olmsted SB, Wells CL, Galan JE. Contact with epithelial cells induces the formation of surface appendages on Salmonella Typhimurium. Cell. 1994;76:717–724. doi: 10.1016/0092-8674(94)90510-X. PubMed DOI

Zhou D, Galan J. Salmonella entry into host cells: the work in concert of type III secreted effector proteins. Microbes Infect. 2001;3:1293–1298. doi: 10.1016/S1286-4579(01)01489-7. PubMed DOI

Freeman JA, Ohl ME, Miller SI. The Salmonella enterica serovar typhimurium translocated effectors SseJ and SifB are targeted to the Salmonella-containing vacuole. Infect Immun. 2003;71:418–427. doi: 10.1128/IAI.71.1.418-427.2003. PubMed DOI PMC

Verreck FA, De Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, Waal-Malefyt R, Ottenhoff TH. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci U S A. 2004;101:4560–4565. doi: 10.1073/pnas.0400983101. PubMed DOI PMC

Boldrick JC, Alizadeh AA, Diehn M, Dudoit S, Liu CL, Belcher CE, Botstein D, Staudt LM, Brown PO, Relman DA. Stereotyped and specific gene expression programs in human innate immune responses to bacteria. Proc Natl Acad Sci U S A. 2002;99:972–977. doi: 10.1073/pnas.231625398. PubMed DOI PMC

Nau GJ, Richmond JF, Schlesinger A, Jennings EG, Lander ES, Young RA. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci U S A. 2002;99:1503–1508. doi: 10.1073/pnas.022649799. PubMed DOI PMC

Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol. 2008;181:3733–3739. PubMed

Hoffmann R, van Erp K, Trulzsch K, Heesemann J. Transcriptional responses of murine macrophages to infection with Yersinia enterocolitica. Cell Microbiol. 2004;6:377–390. doi: 10.1111/j.1462-5822.2004.00365.x. PubMed DOI

Pavlova B, Volf J, Ondrackova P, Matiasovic J, Stepanova H, Crhanova M, Karasova D, Faldyna M, Rychlik I. SPI-1-encoded type III secretion system of Salmonella enterica is required for the suppression of porcine alveolar macrophage cytokine expression. Vet Res. 2011;42:16. doi: 10.1186/1297-9716-42-16. PubMed DOI PMC

Datsenko KA, Wanner BL. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A. 2000;97:6640–6645. doi: 10.1073/pnas.120163297. PubMed DOI PMC

Rychlik I, Karasova D, Sebkova A, Volf J, Sisak F, Havlickova H, Kummer V, Imre A, Szmolka A, Nagy B. Virulence potential of five major pathogenicity islands (SPI-1 to SPI-5) of Salmonella enterica serovar Enteritidis for chickens. BMC Microbiol. 2009;9:268. doi: 10.1186/1471-2180-9-268. PubMed DOI PMC

Ibarra JA, Knodler LA, Sturdevant DE, Virtaneva K, Carmody AB, Fischer ER, Porcella SF, Steele-Mortimer O. Induction of Salmonella pathogenicity island 1 under different growth conditions can affect Salmonella-host cell interactions in vitro. Microbiology. 2010;156:1120–1133. doi: 10.1099/mic.0.032896-0. PubMed DOI PMC

Ito CY, Kazantsev AG, Baldwin AS. Three NF-kappa B sites in the I kappa B-alpha promoter are required for induction of gene expression by TNF alpha. Nucleic Acids Res. 1994;22:3787–3792. doi: 10.1093/nar/22.18.3787. PubMed DOI PMC

Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H, Claussen B, Forster I, Brombacher F. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity. 2004;20:623–635. doi: 10.1016/S1074-7613(04)00107-4. PubMed DOI

Corna G, Campana L, Pignatti E, Castiglioni A, Tagliafico E, Bosurgi L, Campanella A, Brunelli S, Manfredi AA, Apostoli P, Silvestri L, Camaschella C, Rovere-Querini P. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica. 2010;95:1814–1822. doi: 10.3324/haematol.2010.023879. PubMed DOI PMC

Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 1999;10:137–142. doi: 10.1016/S1074-7613(00)80014-X. PubMed DOI

Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med. 1992;176:287–292. doi: 10.1084/jem.176.1.287. PubMed DOI PMC

Welch JS, Escoubet-Lozach L, Sykes DB, Liddiard K, Greaves DR, Glass CK. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J Biol Chem. 2002;277:42821–42829. doi: 10.1074/jbc.M205873200. PubMed DOI

Bruun CS, Leifsson PS, Johansen LK, Jensen HE, Nielsen J, Fredholm M. Expression of matrix Metalloproteinase-9 and −12 in Porcine lung infections. J Comp Pathol. 2012;146:253–257. doi: 10.1016/j.jcpa.2011.05.005. PubMed DOI

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034. PubMed PMC

Volf J, Boyen F, Faldyna M, Pavlova B, Navratilova J, Rychlik I. Cytokine response of porcine cell lines to Salmonella enterica serovar typhimurium and its hilA and ssrA mutants. Zoonoses Public Health. 2007;54:286–293. doi: 10.1111/j.1863-2378.2007.01064.x. PubMed DOI

von der Hardt K, Kandler MA, Fink L, Schoof E, Dotsch J, Brandenstein O, Bohle RM, Rascher W. High frequency oscillatory ventilation suppresses inflammatory response in lung tissue and microdissected alveolar macrophages in surfactant depleted piglets. Pediatr Res. 2004;55:339–346. doi: 10.1203/01.PDR.0000106802.55721.8A. PubMed DOI

Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000;132:365–386. PubMed

Sarkar S, Han J, Sinsimer KS, Liao B, Foster RL, Brewer G, Pestka S. RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IkappaB kinase complex in monocytes. Mol Cell Biol. 2011;31:602–615. doi: 10.1128/MCB.00835-10. PubMed DOI PMC

El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, Konig T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol. 2008;9:1399–1406. doi: 10.1038/ni.1671. PubMed DOI PMC

Santos RL, Raffatellu M, Bevins CL, Adams LG, Tukel C, Tsolis RM, Baumler AJ. Life in the inflamed intestine. Salmonella style. 2009;17:498–506. doi: 10.1016/j.tim.2009.08.008. PubMed DOI PMC

Thiennimitr P, Winter SE, Winter MG, Xavier MN, Tolstikov V, Huseby DL, Sterzenbach T, Tsolis RM, Roth JR, Baumler AJ. Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc Natl Acad Sci U S A. 2011;108:17480–17485. doi: 10.1073/pnas.1107857108. PubMed DOI PMC

Probiotic bacteria of wild boar origin intended for piglets - An in vitro study

Characterization of Porcine Monocyte-Derived Macrophages Cultured in Serum-Reduced Medium

The Role of Antibodies Against the Crude Capsular Extract in the Immune Response of Porcine Alveolar Macrophages to In Vitro Infection of Various Serovars of Glaesserella (Haemophilus) parasuis

Bovine lactoferrin free of lipopolysaccharide can induce a proinflammatory response of macrophages

Evaluation of in vitro and in vivo anti-inflammatory activity of biologically active phospholipids with anti-neoplastic potential in porcine model