title: β-Adrenergic-stimulated macrophages: Comprehensive localization in the M1-M2 spectrum.
abstract: β-Adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that β-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine β-adrenergic-stimulated macrophages within a wider M1-M2 spectrum. Results show that β-adrenergic-stimulated macrophages did not fit entirely into any one pre-defined category of the M1-M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located β-adrenergic-stimulated macrophages firmly on the M2 side of the M1-M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through β2-adrenergic receptors and were associated with CREB, C/EBPβ, and ATF transcription factor pathways but not with established M1-M2 STAT pathways. Thus, β-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1-M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages.
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: dlamkin@ucla.edu.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Lamkin
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Hsin-Yun
authors.initials: HY
authors.lastname: Ho
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Tiffany H
authors.initials: TH
authors.lastname: Ong
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Carly K
authors.initials: CK
authors.lastname: Kawanishi
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stoffers
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Ahlawat
authors.affiliation: Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jeffrey C Y
authors.initials: JCY
authors.lastname: Ma
authors.affiliation: Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jesusa M G
authors.initials: JMG
authors.lastname: Arevalo
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow; D019295:Computational Biology / Q000379:methods*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol
keywords: Bioinformatics; CREB; M1-M2 spectrum; Macrophage; Transcriptome; β-Adrenergic