Article

Obstacles and opportunities for understanding macrophage polarization

Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, TN 38105, USA.
Journal of leukocyte biology (Impact Factor: 4.99). 03/2011; 89(4):557-63. DOI: 10.1189/jlb.0710409
Source: PubMed

ABSTRACT Macrophages are now routinely categorized into phenotypic subtypes based on gene expression induced in response to cytokine and pathogen-derived stimulation. In the broadest division, macrophages are described as being CAMs (M1 macrophages) or AAMs (M2 macrophages) based on their exposure to TLR and IFN signals or Th2 cytokines, respectively. Despite the prolific use of this simple classification scheme, little is known about the precise functions of effector molecules produced by AAMs, especially how representative the CAM and AAM subtypes are of tissue macrophages in homeostasis, infection, or tissue repair and how plasticity in gene expression regulates macrophage function in vivo. Furthermore, correlations between mouse and human tissue macrophages and their representative subtypes are lacking and are a major barrier to understanding human immunity. Here, we briefly summarize current features of macrophage polarization and discuss the roles of various macrophage subpopulations and macrophage-associated genes in health and disease.

0 Followers
 · 
125 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Acquisition of the M1 or M2 phenotypes by microglia has been shown to occur during the development of pathological conditions, with M1 activation being widely involved in neurotoxicity in relation with the anatomical localization and the reactivity of subtypes of microglia cells. On the contrary, little is known on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4), the typical M2a polarization signal for peripheral macrophages.Methods Recombinant mouse IL4 was injected in the third cerebral ventricle of mice to induce brain alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to be up-regulated by IL4 in peripheral macrophages, together with additional polarization markers, were evaluated in the striatum and frontal cortex at different time intervals after central administration of IL4; in parallel, M2a protein expression was evaluated in tissue extracts and at the cellular level.ResultsOur results show that the potency and temporal profile of IL4-mediated M2a gene induction vary depending on the gene analyzed and according to the specific brain area analyzed, with the striatum showing a reduced M2a response compared with the frontal cortex, as further substantiated by assays of polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold level, underscoring the potency of this specific IL4 signaling pathway in the brain. In addition, immunochemistry assays demonstrated the localization of the M2 response specifically to microglia cells and, more interestingly, the existence of a subpopulation of microglia cells amenable to undergoing M2a polarization in the healthy mouse brain.Conclusions These results show that the responsiveness of brain macrophages to centrally administered IL4 may vary depending on the gene and brain area analyzed, and that M2a polarization can be ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical pathways that enable microglia to undergo M2a activation represent key aspects for understanding the physiopathology of neuroinflammation and for developing novel therapeutic and diagnostic agents.
    Journal of Neuroinflammation 12/2014; 11(1):1031. DOI:10.1186/s12974-014-0211-6 · 4.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age-dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-α and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 × 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-α, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-κB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression.
    PLoS ONE 02/2015; 10(2):e0116533. DOI:10.1371/journal.pone.0116533 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Seminars in Immunology 04/2015; DOI:10.1016/j.smim.2015.03.013 · 6.12 Impact Factor