Mismatch between circulating cytokines and spontaneous cytokine production by leukocytes in hyperinflammatory COVID-19

Abstract

The disease COVID-19 has developed into a worldwide pandemic. Hyperinflammation and high levels of several cytokines, for example, IL-6, are observed in severe COVID-19 cases. However, little is known about the cellular origin of these cytokines. Here, we investigated whether circulating leukocytes from patients with COVID-19 had spontaneous cytokine production. Patients with hyperinflammatory COVID-19 (n = 6) and sepsis (n = 3) were included at Skåne University Hospital, Sweden. Healthy controls were also recruited (n = 5). Cytokines were measured in COVID-19 and sepsis patients using an Immulite immunoassay system. PBMCs were cultured with brefeldin A to allow cytokine accumulation. In parallel, LPS was used as an activator. Cells were analyzed for cytokines and surface markers by flow cytometry. High levels of IL-6 and measurable levels of IL-8 and TNF, but not IL-1 , were observed in COVID-19 patients. Monocytes from COVID-19 patients had spontaneous production of IL-1 and IL-8 (P = 0.0043), but not of TNF and IL-6, compared to controls. No spontaneous cytokine production was seen in lymphocytes from either patients or controls. Activation with LPS resulted in massive cytokine production by monocytes from COVID-19 patients and healthy controls, but not from sepsis patients. Finally, monocytes from COVID-19 patients produced more IL-1 than from healthy controls (P = 0.0087) when activated. In conclusion, monocytes contribute partly to the ongoing hyperinflammation by production of IL-1 and IL-8. Additionally, they are responsive to further activation. This data supports the notion of IL-1 blockade in treatment of COVID-19. However, the source of the high levels of IL-6 remains to be determined.

Changes of Damage Associated Molecular Patterns in COVID-19 Patients

“…Although the anti-viral immune response is crucial for eliminating SARS-CoV-2, a robust and persistent anti-viral immune response can also cause a massive production of inflammatory cytokines and damage to host tissues. [ 5 – 8 ] Indeed, the overproduction of cytokines caused by aberrant immune activation (termed a cytokine storm) is hypothesized to be a major cause of disease progression and eventual death in patients with COVID-19. [ 9 ]…”

Preexisting and inducible endotoxemia as crucial contributors to the severity of COVID-19 outcomes

“…One of these feedback loops connected to LPS is endotoxin tolerance (i.e., reduced cellular responses to repeated applications of endotoxins), which, under quasi-physiological conditions, suppresses the induced endotoxemia. A closer examination of cytokine expression in COVID-19 versus sepsis patients reveals a nonobvious behavior [ 20 ]. Whereas a relatively low spontaneous production of some cytokines is observed in monocytes of COVID-19 patients with hyper-inflammation versus controls and in patients with sepsis, additional LPS stimulation caused a strong further enhancement of expression of all cytokines (especially of interleukin [IL]-1β) in COVID-19, but not in septic patients.…”

Ascorbic acid attenuates activation and cytokine production in sepsis-like monocytes

“…In addition, monocytes display a suppressive and exhausted phenotype and when exposed to LPS they respond poorly with production of pro-inflammatory cytokines, as opposed to monocytes from patients with hyperinflammatory COVID-19 (8). Thus, these data suggest that AA might not target only the pro-inflammatory aspect (inflammatory cytokine production) but also the immunosuppressive phenotype (CD16 and CD163) of monocytes in sepsis.…”