Hydroxychloroquine in rheumatic autoimmune disorders and beyond.

Eliise Laura Nirk,Mario Mauthe,Fulvio Reggiori

doi:10.15252/emmm.202012476

Eliise Laura Nirk, Mario Mauthe + Show 1 more

Open Access

https://doi.org/10.15252/emmm.202012476

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Journal: EMBO molecular medicine	Publication Date: Jul 26, 2020
Citations: 83	License type: CC BY 4.0

Affiliation: University of Groningen

Abstract

Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost‐effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll‐like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro‐inflammatory cytokine production and release, one of the most marked symptoms of RADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs.

Highlights

Antimalarial drugs have a long history, starting around 400 years ago when quinine, a substance in the bark of the cinchona tree, was first used to fight Plasmodium falciparum infections (Woodward & Doering, 1945; Haładyj et al, 2018)
HCQ is nowadays widely used for the treatment of rheumatic autoimmune disorders (RADs) and has shown great success in improving the quality of life of many patients
The beneficial therapeutic effect of HCQ in RADs probably lies in its multifaceted properties, which makes it a promising candidate in other medical fields, such as oncology (Onorati et al, 2018) and microbiology (Savarino et al, 2003; Cortegiani et al, 2020; Yao et al, 2020)

Summary

Introduction

Antimalarial drugs have a long history, starting around 400 years ago when quinine, a substance in the bark of the cinchona tree, was first used to fight Plasmodium falciparum infections (Woodward & Doering, 1945; Haładyj et al, 2018). Inhibition of lysosomal activity and autophagy CQ and HCQ are weak bases that cross cell membranes and accumulate in acidic subcellular compartments such as lysosomes and endosomes, where they remain trapped in a protonated state (Ohkuma & Poole, 1978) This leads to a pH increase in lysosomes from 4 to 6, causing inhibition of acidic proteases and other enzymes within the endolysosomal compartments (Fig 1A) (Ohkuma & Poole, 1978; Poole & Ohkuma, 1981; Ziegler & Unanue, 1982; Haładyj et al, 2018). CQ and HCQ increase pH levels within the Golgi stacks This causes functional alterations of this organelle that possibly contribute to the cellular effects of these two drugs, e.g. by impairing transforming growth factor beta (TGF-b) activity (Perkett et al, 2006; Rivinoja et al, 2009; Mauthe et al, 2018). CQ and HCQ decrease the acidity of lysosomes (Seglen et al, 1979; Poole & Ohkuma, 1981; Mizushima et al, 2010), the 2 of 17 EMBO Molecular Medicine e12476 | 2020

C B and T cells

Conclusions