The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19

Robinson, Philip C; Liew, David; Liew, Jean W; Monaco, Claudia; Richards, Duncan; Shivakumar, Senthuran; Tanner, Helen; Feldmann, Marc

doi:10.1016/j.medj.2020.11.005

Cited by 107 publications

(121 citation statements)

References 84 publications

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“…To define the factors that shape disease-associated macrophage states in affected tissues, we generated human blood-derived macrophages from four donors and activated them with eight defined mixtures of inflammatory factors, focusing particularly on the effects of antiviral interferons (IFN-β and IFN-γ) and pro-inflammatory cytokines such as TNF that mediate CRS and tissue pathology in RA and IBD [ 40 ] (Fig. 3 a, Additional file 2 : Figure S7a, “ Methods ”).…”

Section: Resultsmentioning

confidence: 99%

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

et al. 2021

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Background Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Methods To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. Results We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. Conclusions Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.

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Section: Resultsmentioning

confidence: 99%

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

et al. 2021

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“…We analyzed TNF-α, IL-6 and CCL2. TNF-α [ 60 ] and IL-6 [ 32 , 61 ] have been identified as major inducers of the SARS-CoV-2 hyperinflammatory response. CCL2 is considered a fibrosis-associated chemokine involved in several lung inflammatory disorders including SARS, asthma and pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

et al. 2021

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The key link between renin–angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.

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“…In the face of this body of compelling evidence, there is a compelling need for a full-scale evaluation of TNF inhibitors through an RCT. 219 However, there are safety concerns about secondary bacterial infection following the administration of TNF inhibitors. 220 …”

Section: Mitigation and Therapeutic Intervention Of Covid-19-induced mentioning

confidence: 99%

Attenuating the Effects of Novel COVID-19 (SARS-CoV-2) Infection-Induced Cytokine Storm and the Implications

Rowaiye¹,

Okpalefe²,

Adejoke³

et al. 2021

JIR

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The COVID-19 pandemic constitutes an arduous global health challenge, and the increasing number of fatalities calls for the speedy pursuit of a remedy. This review emphasizes the changing aspects of the COVID-19 disease, featuring the cytokine storm’s pathological processes. Furthermore, we briefly reviewed potential therapeutic agents that may modulate and alleviate cytokine storms. The literature exploration was made using PubMed, Embase, MEDLINE, Google scholar, and China National Knowledge Infrastructure databases to retrieve the most recent literature on the etiology, diagnostic markers, and the possible prophylactic and therapeutic options for the management of cytokine storm in patients hospitalized with COVID-19 disease. The causative agent, severe acute respiratory coronavirus-2 (SARS-CoV-2), continually threatens the efficiency of the immune system of the infected individuals. As the first responder, the innate immune system provides primary protection against COVID-19, affecting the disease’s progression, clinical outcome, and prognosis. Evidence suggests that the fatalities associated with COVID-19 are primarily due to hyper-inflammation and an aberrant immune function. Accordingly, the magnitude of the release of pro-inflammatory cytokines such as interleukin (IL)-1, (IL-6), and tumor necrosis alpha (TNF-α) significantly differentiate between mild and severe cases of COVID-19. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for diagnosis and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19. The prophylaxis and the rapid treatment of cytokine storm by clinicians will significantly enhance the fight against the dreaded COVID-19 disease.

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The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19

Cited by 107 publications

References 84 publications

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

Attenuating the Effects of Novel COVID-19 (SARS-CoV-2) Infection-Induced Cytokine Storm and the Implications

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