title: IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis.
abstract: OBJECTIVE
  Osteoclasts (OC) originate from monocytes/macrophages and play a critical role in the development of ankylosing spondylitis (AS). Receptor activator of NF-kB ligand (RANKL) is critical for the differentiation and maturation of OC from monocytes/macrophages, the underlying mechanisms of which processes have not been completely elucidated. Interleukin 4 (IL-4) attenuates the pathogenesis of AS via ill-defined mechanisms.
  
  
  METHODS
  We used a proteoglycan-induced arthritis (PGIA) model in Balb/c mice to study AS in humans. We injected IL-4 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, clinical and pathological arthritis severity and PET tracer uptake. We isolated and analyzed the number and polarization of macrophages in the articular cavity before and after IL-4 treatment. We analyzed RANKL levels in macrophage subtypes. We then isolated bone-marrow derived macrophages and treated them with IL-4 in vitro, with or without histone deacetylase inhibitors trichostatin A (TSA), and then analyzed the polarization of cultured macrophages before and after IL-4 treatment and RANKL levels in macrophage subtypes.
  
  
  RESULTS
  IL-4 treatment decreased the incidence and severity of arthritis in a mouse AS model, and polarized macrophages from a classical M1 subtype to an M2 subtype in vivo and in vitro. RANKL was predominantly produced by M1, but not by M2 macrophages. IL-4-mediated inhibition of RANKL in macrophages was abolished by TSA.
  
  
  CONCLUSIONS
  Our data suggest that the therapeutic effects of IL-4 on AS may result from a M1-to-M2 macrophage polarization and its inhibition of RANKL expression on macrophages, possibly through enhanced histone deacetylation.
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Shishui
authors.initials: S
authors.lastname: Lin
authors.forename: Meiguang
authors.initials: M
authors.lastname: Qiu
authors.forename: Jianting
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053245:RANK Ligand; D015847:Interleukin-4; C012589:trichostatin A