Mode of action of hydroxychloroquine in RA—evidence of an inhibitory effect on toll-like receptor signaling (original) (raw)

Antimalarial drugs have been used for many years to treat rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The two most commonly used antimalarial agents (chloroquine and hydroxychloroquine) have been compared with placebo in randomized, controlled trials in patients with RA, and significant efficacy has been documented.1 Hydroxychloroquine combined with methotrexate and sulfasalazine has also been shown to be significantly more effective than methotrexate monotherapy.2 Although the efficacy of antimalarial agents seems to be lower than that of the first-line disease-modifying drug methotrexate, hydroxychloroquine remains a popular therapy for RA because of its excellent safety profile.

In contrast to the well-documented safety and efficacy of hydroxychloroquine, its mechanism of action is poorly understood. It has been proposed that the marked accumulation of chloroquine and hydroxychloroquine in the lysosomal compartment is responsible for the therapeutic effects of these drugs. Chloroquine is lipophilic and, therefore, readily enters cells. Chloroquine is also a weak base, and so high concentrations of chloroquine can elevate the pH within lysosomes, which results in inactivation of acid proteases. Chloroquine was shown to interfere with receptor function, to inhibit intracellular processing and secretion of proteins, to decrease lymphocyte proliferation and to interfere with natural killer T-cell activity.3 Chloroquine was also shown to decrease the production of various cytokines in vitro. The molecular pathways leading to these effects are, however, unclear. In relation to the inhibitory effects of chloroquine on the production of cytokines, it was reported that chloroquine inhibits the production of tumor necrosis factor in human peripheral blood mononuclear cells stimulated with lipopolysaccharide.4 In a subsequent study, Weber and colleagues elegantly demonstrated that chloroquine interferes with the phosphorylation of extracellular signal-regulated kinases (ERKs), and prevents activation of mitogen-activated protein kinases. This inhibition of ERK activation by chloroquine was shown not only to interfere with lipopolysaccharide-induced production of tumor necrosis factor, but also to sensitize HeLa cells to Fas (also known as CD95)-mediated apoptosis;5 a similar effect for hydroxychloroquine was most recently demonstrated in rheumatoid synovial fibroblasts.6 Whereas both chloroquine and hydroxychloroquine inhibit lipopolysaccharide-induced ERK signaling in the cytoplasm, recent data indicate that these agents might also interfere with Toll-like receptor (TLR)-dependent cell activation within endosomes. In a seminal paper, Leadbetter and colleagues demonstrated that rheumatoid factor (RF) production by activated B cells can be triggered by chromatin-containing immune complexes. Use of transgenic RF-positive mice demonstrated that RF production required not only the recognition of IgG-Fc, via the B-cell receptor, but also an additional signal via TLR9.7 In their transgenic system, the activation of TLR9 by the double-stranded (ds)DNA contained in the immune complex delivered a second signal, which was required for full activation of the B cells and for production of RF. This mechanism was proposed as an explanation for the predominance of antinuclear antibodies in patients with SLE. Moreover, this explanation provided a mechanism for the breakage of immune tolerance to autoantigens (in this case nuclear antigens). Interestingly, in this study chloroquine was able to block RF production induced by chromatin-containing immune complexes. TLR9, like TLRs 3, 7 and 8, are located intracellularly in the endosomal compartment. Agents that interfere with endosomal acidification, such as chloroquine or hydroxychloroquine, might block signaling by these intracellular TLRs. These data, therefore, suggest that the actions of antimalarial agents in rheumatic diseases such as RA and SLE are, at least partly, related to their inhibitory effect on TLR signaling.

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Authors and Affiliations

  1. Arthritis Group at the Department of Rheumatology of the University Hospital of Zurich,
    Diego Kyburz, Fabia Brentano & Steffen Gay
  2. Department of Rheumatology,
    Diego Kyburz, Fabia Brentano & Steffen Gay
  3. Center of Experimental Rheumatology at the University of Zurich, Switzerland
    Diego Kyburz, Fabia Brentano & Steffen Gay

Authors

  1. Diego Kyburz
  2. Fabia Brentano
  3. Steffen Gay

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Correspondence toDiego Kyburz.

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The authors declare no competing financial interests.

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Kyburz, D., Brentano, F. & Gay, S. Mode of action of hydroxychloroquine in RA—evidence of an inhibitory effect on toll-like receptor signaling.Nat Rev Rheumatol 2, 458–459 (2006). https://doi.org/10.1038/ncprheum0292

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