Table 2.

Mechanisms of action of hydroxychloroquine.

HCQ/CQ Mechanisms of action	Molecular mechanism(s) demonstrated	Potential consequence(s) in SLE pathogenesis	References
Inhibition of TLR-7 and TLR-9	Suppression of endosomal TLR activation direct binding of antimalarials to nucleic acids rather than inhibition of endosomal acidification	Inhibition of IFN-I production by pDC	Lamphier et al. 41 Kužnik et al. 42 Gardet et al. 43
Inhibition of cyclic GMP-AMP synthase (cGAS) activity	Inhibition of (cGAS)-STING pathway	Inhibition of IFN-I production	An et al. 44
Inhibition of autophagy	Blockade of autophagosome fusion with the lysosome	Inhibition of MHC class II-mediated autoantigen presentation by antigen-presenting cells to CD4+ T cells	Levy et al. 51 Schrezenmeier and Dörner 39
Inhibition of antigen presentation	CQ has been shown to inhibit presentation of antigen in vitro by affecting invariant chain dissociation from MHC class II	Inhibition of MHC class II-mediated autoantigen presentation by antigen-presenting cells to CD4+ T cells	Humbert et al. 52
Inhibition of inflammatory cytokine production and angiogenesis	Decrease mRNA expression of IL-1β, IL-6, and TNF-α in CLE skin lesions Decrease VEGF expression in CLE skin lesion	Decrease of local inflammation Decrease of mononuclear cellular infiltrate in the skin Inhibition of angiogenesis	Wozniacka et al. 45 Lesiak et al. 46 Zeidi et al. 47
Photoprotection against UVA and UVB	Increase of c-Jun mRNA expression Decrease mRNA expression of IL-1β, IL-6, and TNF-α in CLE skin lesions Decrease UV-induced ICAM-1 expression in keratinocytes CQ inhibits lipid peroxidation and decrease UVB and induces phospholipase A2 activity in skin Decrease of the number of cutaneous HLA-DR+ and CD1a+ cells after UVB irradiation	Decrease of local inflammation, apoptosis, and necrosis of keratinocytes Decrease of the release of skin nucleic acids Decrease of the mononuclear cellular infiltrate in the skin	Nguyen et al. 65 Sjolin-Forsberg et al. 59 Wozniacka et al. 64 Wozniacka et al. 60 Bondeson and Sundler 61 el Tahir et al. 62 Segal-Eiras et al. 63
Decrease NET formation and circulating DNA	HCQ inhibits NETs formation in vitro Circulating DNA significantly decreases after CQ treatment	Decrease of circulating nucleic acids Inhibition of IFN-I production Decrease of LL37 formation and inflammasome activation Decrease of MMP-9 and reduced endothelial cell death	Smith et al. 48 Smith and Kaplan 49 Cepika et al. 50
Change in T-cell polarization	HCQ decreases Th17-related cytokines HCQ decreases Th22-related cytokines HCQ blood concentrations correlate negatively with the percentage of CD45RO+ CD4+ cells	Decrease of mononuclear cellular infiltrate in the skin Decrease of survival and proliferation of human B cells as well as the differentiation of B cells into antibody-producing cells Recruitment and activation of inflammatory cells with tissue damage Inhibition of angiogenesis	Silva et al. 53 Zhao et al. 54 Shin et al. 55 Sailler et al. 56
Inhibition of NK cells	Decrease proliferation, cytotoxicity, and cytokine production of NK cells	Possible deleterious effects of NK cells in SLE: tissue infiltration, proinflammatory cytokine production: IFNγ, IL-15	Spada et al. 57 Fox 58

cGAS, cyclic GMP-AMP synthase; CLE, cutaneous lupus erythematosus; CQ, chloroquine; DC, dendritic cells; HCQ, hydroxychloroquine; ICAM, intercellular adhesion molecule-1; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NETs, neutrophil extracellular traps; NK, natural killer; SLE, systemic lupus erythematosus; STING, stimulator of interferon genes; Th, T helper; TLRs, Toll-like receptors; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.