title: Dissonant response of M0/M2 and M1 bone-marrow-derived macrophages to RhoA pathway interference.
abstract: Macrophages have a multitude of functions in innate and adaptive immune response and organ and tissue homeostasis. Many experimental studies are performed on bone-marrow-derived macrophages differentiated in vitro into M1 (inflammatory) and M2 (anti-inflammatory) subtypes that express different molecular markers pertaining to their prospective functions. Macrophage phenotype, polarity and functions depend on the actin cytoskeleton, which is regulated by small GTPase RhoA, its downstream effector ROCK, and non-apoptotic Caspase-3. We generated transgenic mice with the macrophage-specific deletion of RhoA and compared the effect of Rho pathway interference (RhoA deletion and ROCK and Caspase-3 inhibition) on the phenotype, polarity and expression of subtype-specific molecular markers of bone-marrow-derived M0, M1 and M2 macrophages. We show that M0 and M2 macrophages have a radically different phenotype and polarity from M1 macrophages, and that this is mirrored in dissonant response to RhoA pathway interference. The RhoA pathway interference induces extreme elongation (hummingbird phenotype) of M0 and M2 but not M1 macrophages and inhibits the expression of M2-specific but not M1-specific molecular markers. These dramatic differences in the response of M0/M2 versus M1 macrophages to the same molecular cues ought to be important considerations in the interpretation of experimental data and therapeutic use of bone-marrow-derived macrophages.
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
authors.forename: Yianzhu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Minze
authors.affiliation: CNRS UMR 6290, Institute of Genetics and Development of Rennes, Cell Cycle Group, IFR 140 GFAS, Rennes, France.|University of Rennes 1, Faculty of Medicine, 35043, Rennes, France.
authors.forename: Jacek Z
authors.initials: JZ
authors.lastname: Kubiak
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.
authors.forename: Xian C
authors.initials: XC
authors.lastname: Li
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA.|Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, Tex., USA.
authors.forename: Rafik M
authors.initials: RM
authors.lastname: Ghobrial
authors.affiliation: The Houston Methodist Research Institute, Houston, Tex., USA. mkloc@houstonmethodist.org.|Department of Surgery, The Houston Methodist Hospital, 6550 Fannin Street, Houston, TX 77030, USA. mkloc@houstonmethodist.org.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloc
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D016764:Cell Polarity / Q000187:drug effects; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013623:Tail; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D015415:Biomarkers; D061945:Caspase Inhibitors; D011725:Pyridines; C108830:Y 27632; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein
keywords: Actin; Bone-marrow-derived macrophages; Caspase-3; ROCK; RhoA