Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4–MyD88 Complex

Abstract

Dimethyl fumarate (DMF) is a prescribed treatment for multiple sclerosis and has also been used to treat psoriasis. The electrophilicity of DMF suggests that its immunosuppressive activity is related to the covalent modification of cysteine residues in the human proteome. Nonetheless, our understanding of the proteins modified by DMF in human immune cells and the functional consequences of these reactions remains incomplete. In this study, we report that DMF inhibits human plasmacytoid dendritic cell function through a mechanism of action that is independent of the major electrophile sensor NRF2. Using chemical proteomics, we instead identify cysteine 13 of the innate immune kinase IRAK4 as a principal cellular target of DMF. We show that DMF blocks IRAK4–MyD88 interactions and IRAK4-mediated cytokine production in a cysteine 13–dependent manner. Our studies thus identify a proteomic hotspot for DMF action that constitutes a druggable protein–protein interface crucial for initiating innate immune responses.

Targeting immunometabolism as an anti-inflammatory strategy

“…39 Using mass spectrometry, Piroli et al recently identified 24 novel DMFmodified proteins in neurons and astrocytes, including cofilin-1, tubulin and collapsing response mediator protein 2 (CRMP2). 40 Using human plasmacytoid DCs, an important cell type in systemic lupus erythematosus (SLE), as well as in psoriasis and MS, Zaro et al recently described anti-inflammatory effects of DMF that are dependent on cysteine-13 of IRAK4, 41 a key enzyme in IL-1, IL-18 and Toll-like receptor (TLR) signaling. Covalent modification at this site by DMF prevents the assembly of IRAK4 and the adapter protein MyD88, leading to a reduced production of cytokines and chemokines including IFN-α and TNFα, thereby identifying cysteine 13 on IRAK4 as a vital regulatory point for adequate innate immune responses and potentially a novel therapeutic target for suppressing an overactive immune system.…”

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

“…Although developed recently, IRAK4 inhibitors are under assessment in psoriasis, whilst in rheumatoid arthritis a completed phase II clinical trial has demonstrated clinical improvement (142). Interestingly, dimethyl fumarate, already of proven clinical efficacy in treating both multiple sclerosis and psoriasis, is not only a direct inhibitor of IRAK4 but also suppresses innate proinflammatory cytokines in pDCs, providing a strong mechanistic rationale for its recently proposed repurposing for COVID-19 "cytokine storm" (143,144). Lowgrade inflammation is common in autoimmunity (145), with an inflammatory signature similar to COVID-19 (146).…”

Electrophile Modulation of Inflammation: A Two-Hit Approach

“…More specifically, T-cell activation is inhibited by limiting subsequent CD28 kinase signaling through DMF adduction to PKCθ cysteine residues [140]. Additionally, DMF inhibits IRAK4-MyD88 interaction by adducting to Cys 13 of IRAK4 in human innate immune cells [141]. Inhibition of NF-κB activation by way of IRAK4 limits • NO production by iNOS.…”