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Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.

ABSTRACT: Production of type I interferon (IFN; IFN-alphabeta) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-gamma) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-alphabeta and IFN-gamma occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN-gamma treatment as a result of down-regulation of the IFN-gamma receptor (IFNGR). The soluble factor responsible for these effects was identified as host IFN-alphabeta. Accordingly, macrophages and dendritic cells (DCs) showed reduced IFNGR1 expression and reduced responsiveness to IFN-gamma during systemic infection of IFN-alphabeta-responsive mice. Furthermore, the increased resistance of mice lacking the IFN-alphabeta receptor (IFNAR(-/-)) to L. monocytogenes correlated with increased expression of IFN-gamma-dependent activation markers by macrophages and DCs and was reversed by depletion of IFN-gamma. Thus, IFN-alphabeta produced in response to bacterial infection and other stimuli antagonizes the host response to IFN-gamma by down-regulating the IFNGR. Such cross talk permits prioritization of IFN-alphabeta-type immune responses and may contribute to the beneficial effects of IFN-beta in treatment of inflammatory diseases such as multiple sclerosis.

SUBMITTER: Rayamajhi M

PROVIDER: S-EPMC2822610 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.

Rayamajhi Manira M Humann Jessica J Penheiter Kristi K Andreasen Karl K Lenz Laurel L LL

The Journal of experimental medicine 20100201 2

Production of type I interferon (IFN; IFN-alphabeta) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-gamma) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-alphabeta and IFN-gamma occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN-gamma treatment as a result of down-regulation of the IFN-gamma receptor ( ...[more]

PMID: 20123961

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Project description:BackgroundTumor-associated macrophages (TAMs) are an important subset of innate immune cells in the tumor microenvironment, and they are pivotal regulators of tumor-promoting inflammation and tumor progression. Evidence has proven that TAM numbers are substantially increased in cancers, and most of these TAMs are polarized toward the alternatively activated M2 phenotype; Thus, these TAMs strongly promote the progression of cancer diseases. Type 1 innate lymphocytes (ILC1s) are present in high numbers in intestinal tissues and are characterized by the expression of the transcription factor T-bet and the secretion of interferon (IFN)-γ, which can promote macrophages to polarize toward the classically activated antitumor M1 phenotype. However, the relationship between these two cell subsets in colon cancer remains unclear.MethodsFlow cytometry was used to determine the percentages of M1-like macrophages, M2-like macrophages and ILC1s in colon cancer tissues and paracancerous healthy colon tissues in the AOM/DSS-induced mouse model of colon cancer. Furthermore, ILC1s were isolated and bone marrow-derived macrophages were generated to analyze the crosstalk that occurred between these cells when cocultured in vitro. Moreover, ILC1s were adoptively transferred or inhibited in vivo to explore the effects of ILC1s on tumor-infiltrating macrophages and tumor growth.ResultsWe found that the percentages of M1-like macrophages and ILC1s were decreased in colon cancer tissues, and these populations were positively correlated. ILC1s promoted the polarization of macrophages toward the classically activated M1-like phenotype in vitro, and this effect could be blocked by an anti-IFN-γ antibody. The in vivo results showed that the administration of the Group 1 innate lymphocyte-blocking anti-NK1.1 antibody decreased the number of M1-like macrophages in the tumor tissues of MC38 tumor-bearing mice and promoted tumor growth, and adoptive transfer of ILC1s inhibited tumors and increased the percentage of M1-like macrophages in MC38 tumor-bearing mice.ConclusionsOur studies preliminarily prove for the first time that ILC1s promote the activation of M1-like macrophages by secreting IFN-γ and inhibit the progression of colon cancer, which may provide insight into immunotherapeutic approaches for colon cancer.

Project description:MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155-/-) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155-/- mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155-/- mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155-/- microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155-/- microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

Project description:Listeria monocytogenes (LM) is a Gram-positive, facultative intracellular bacterium responsible for disseminated infections in immunocompromised individuals which can result in septicaemia and meningitis (1). Effective control of listeriosis requires both innate and adaptive immune responses with the principal mediators of bacterial killing being neutrophils and macrophages (2). Key cytokines driving the innate immune response are IFN-γ (3) and TNF (4), which promote macrophage activation and drive the production of anti-microbial mediators such as reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). Several studies using gene deficient mice demonstrated that ROI and RNI are required for optimal pathogen killing (5-8), but that macrophages also utilise an alternative, unknown mechanism besides ROI and RNI to efficiently control bacterial infection. Mice deficient for the transcription factor NF-IL6 are highly susceptible to a number of intracellular bacterial and fungal infections, including LM (9-12). NF-IL6-deficient mice infected with LM were unable to prevent bacterial dissemination, despite production of nitric oxide (NO), IFN-γ and TNF being equivalent to WT controls (12). From these results, we hypothesized that NF-IL6 acts downstream from IFN-γ and TNF during the activation of macrophage effector functions against LM (2). To facilitate the identification of putative effector genes in this unknown pathway, we compared gene expression profiles of WT and NF-IL6 deficient LM-infected macrophages by differential microarray. REFERENCES 1. Gellin, B. G. & Broome, C. V. (1989) Jama 261, 1313-1320. 2. Brombacher, F. & Kopf, M. (1996) Res Immunol 147, 505-511. 3. Buchmeier, N. A. & Schreiber, R. D. (1985) Proc Natl Acad Sci U S A 82, 7404-7408. 4. Havell, E. A. (1989) J Immunol 143, 2894-2899. 5. Dinauer, M. C., Deck, M. B., & Unanue, E. R. (1997) J Immunol 158, 5581-5583. 6. Endres, R., Luz, A., Schulze, H., Neubauer, H., Futterer, A., Holland, S. M., Wagner, H., & Pfeffer, K. (1997) Immunity 7, 419-432. 7. MacMicking, J. D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D. S., Trumbauer, M., Stevens, K., Xie, Q. W., Sokol, K., Hutchinson, N., et al. (1995) Cell 81, 641-650. 8. Shiloh, M. U., MacMicking, J. D., Nicholson, S., Brause, J. E., Potter, S., Marino, M., Fang, F., Dinauer, M., & Nathan, C. (1999) Immunity 10, 29-38. 9. Pizarro-Cerda, J., Desjardins, M., Moreno, E., Akira, S., & Gorvel, J. P. (1999) J Immunol 162, 3519-3526. 10. Screpanti, I., Romani, L., Musiani, P., Modesti, A., Fattori, E., Lazzaro, D., Sellitto, C., Scarpa, S., Bellavia, D., Lattanzio, G., et al. (1995) Embo J 14, 1932-1941. 11. Sugawara, I., Mizuno, S., Yamada, H., Matsumoto, M., & Akira, S. (2001) Am J Pathol 158, 361-366. 12. Tanaka, T., Akira, S., Yoshida, K., Umemoto, M., Yoneda, Y., Shirafuji, N., Fujiwara, H., Suematsu, S., Yoshida, N., & Kishimoto, T. (1995) Cell 80, 353-361. Keywords: bone marrow derived macrophages, interferon-gamma, macrophage activation, macrophage effector activity, NF-IL6, gene-deficient mouse model, Listeria monocytogenes, intracellular pathogen

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Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.

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Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.

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