Abstract
Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now spread globally. Some patients develop severe complications including multiple organ failure. It has been suggested that excessive inflammation associated with the disease plays major role in the severity and mortality of COVID-19. To elucidate the inflammatory mechanisms involved in COVID-19, we examined the effects of SARS-CoV-2 spike protein S1 subunit (hereafter S1) on the pro-inflammatory responses in murine and human macrophages. Murine peritoneal exudate macrophages produced pro-inflammatory mediators in response to S1 exposure. Exposure to S1 also activated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. Pro-inflammatory cytokine induction by S1 was suppressed by selective inhibitors of NF-κB and JNK pathways. Treatment of murine peritoneal exudate macrophages and human THP-1 cell-derived macrophages with a toll-like receptor 4 (TLR4) antagonist attenuated pro-inflammatory cytokine induction and the activation of intracellular signaling by S1 and lipopolysaccharide. Similar results were obtained in experiments using TLR4 siRNA-transfected murine RAW264.7 macrophages. In contrast, TLR2 neutralizing antibodies could not abrogate the S1-induced pro-inflammatory cytokine induction in either RAW264.7 or THP-1 cell-derived macrophages. These results suggest that SARS-CoV-2 spike protein S1 subunit activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. Therefore, TLR4 signaling in macrophages may be a potential target for regulating excessive inflammation in COVID-19 patients.
Highlights
Coronavirus disease 2019 (COVID-19), which has spread globally, is an infectious disease caused by a novel type of coronavirus referred as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
Since endotoxin levels of the recombinant protein were less than 0.1 EU/μg protein, we confirmed that 10 pg/ml of LPS, which might be present due to contamination, does not cause tumor necrosis factor-α (TNF-α) mRNA induction in murine peritoneal exudate macrophages (Supplemental Fig. 1B)
This study demonstrated that SARS-CoV-2 spike protein S1 subunit induced production of pro-inflammatory mediators and activation of NFκB and stress-activated mitogen-activated protein kinase (MAPK) signaling in murine primary macrophages
Summary
Coronavirus disease 2019 (COVID-19), which has spread globally, is an infectious disease caused by a novel type of coronavirus referred as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The most frequent symptom of severe COVID-19 is pneumonia, accompanied by fever, cough, and dyspnea [1]. The majority of infected patients either do not experience pneumonia or exhibit mild symptoms, a portion of patients develop critical complications, such as respiratory failure, systemic shock, or multiple organ failure [2]. Growing evidence suggests that excessive host pro-inflammatory responses cause disease severity and mortality in patients [1, 3]. Critically ill patients are characterized by a depletion of tissue-resident alveolar macrophages and a remarkably increased proportion of recruited pro-inflammatory monocyte-derived macrophages in the bronchoalveolar lavage fluid [5]. It is estimated that a decline in clearance of dead lung cells and subsequent diffusion of pro-inflammatory lipid mediators from these cells mediate the dysregulated recruitment and pro-inflammatory activation of monocyte-derived macrophages [6]
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