Anti-TNF-α agents Modulate SARS-CoV-2 Receptors and Increase the Risk of Infection Through Notch-1 Signaling

Abstract

Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.

Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality

“…The increase in ADAM17 in the context of COVID-19 may have other implications that might be explored. For instance, ADAM17 promotes an increase in the pro-inflammatory response by activating signaling pathways such as the notch pathway, regulating proliferation, differentiation, and apoptosis [44,45]. Under viral infection contexts (influenza virus and human papilloma virus), ADAM17 attacks the cellular machinery and deregulates the notch pathway to improve the infection.…”

“…Under viral infection contexts (influenza virus and human papilloma virus), ADAM17 attacks the cellular machinery and deregulates the notch pathway to improve the infection. Recently, it has been postulated that anti-TNF modulators increase the susceptibility to SARS-CoV-2 infection through Notch/IL-6 signaling via TMPRSS2-ADAM17 modulation in a macrophage model [45]. More evidence is required to clarify if this could be a generalized effect in patients with inflammatory diseases [46,47].…”

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis

“…Our present and prior work argues against an early cytokine storm in SARS-CoV-2 ( 2 ), but rather a late cytokine response associated with progressive disease ( 1 ). Evidence from a human, observational study casts doubt on the utility of anti-TNF-alpha therapy for SARS-CoV-2 infection ( 36 ). Yet, emerging evidence suggests potential utility for IL-1 and IL-6 inhibitors ( 37 , 38 ).…”

Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients

“…There have been very few studies on the possible effects of TNF inhibitors on ACE and ACE2. In a small study, ACE2 plasma levels were significantly lower in RA patients on anti-TNF treatment compared to healthy controls (55). In the study of RA, SSc and SLE patients, most antirheumatic treatments did not affect ACE2 levels (45).…”