Li J, Hsu H-C, Mountz JD.
Managing Macrophages in Rheumatoid Arthritis by Reform or Removal.
Current Rheumatology Reports [Internet]. 2012 Aug 2 [cited 2012 Aug 3];
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Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases. Table 1 Novel macrophage-related therapeutic agents for rheumatoid diseases Agent Mechanisms Development phase Reference Antihuman DR5 antibody, TRA-8(CS-1008) Induces apoptosis of targeted cells Preclinical [27••] Tumor necrosis factor-converting enzyme (TACE) inhibitors, TMI-005 and BMS-561392 Inhibits the release of soluble TNF from its membrane-bound precursor Clinical Phase II [51] GM-CSF and GM-CSF receptor antibodies Blocks the binding of GM-CSF to its receptor and downstream signaling Clinical Phase II [3, 11••] JAK inhibitor, Tofacitinib and Ruxolitinib Abrogated TNF-induced STAT1 activation and expression of genes encoding inflammatory chemokines Clinical Phase III [12] Tyrosine kinase inhibitor, Imatinib and mastinib Inhibits tyrosine kinases, including platelet-derived growth factor receptor (PDGFR), Kit, and Fms related kinases Clinical Phase II-III [52, 53] Anti-IL-12/IL-23 monoclonal antibody, ustekinumab Blocking binding of IL-12/23 to their receptors and the downstream signaling Approved for psoriasis and psoriatic arthritis [54] Clodronate liposomes Deplete synovial macrophages by intraarticular administration Open study in patients who were scheduled for knee joint replacement [49].