Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages

Abstract

Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis was further enhanced by glucocorticoids and remained elevated at 3–5 months, but had returned to baseline at 12 months post SARS-CoV-2 infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered exaggerated prostanoid-, type I IFN-, and chemokine responses in post COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint in the monocyte/ macrophage compartment that drives aberrant macrophage effector functions and eicosanoid metabolism, resulting in long-term immune aberrations in patients recovering from mild COVID-19.

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity

“…These findings are indicative of dysregulated crosstalk between T cells and DCs (Hivroz et al, 2012) and granulocytes with other immune cells (Lourda et al, 2021), which could explain the insufficient control of the viral replication (Saichi et al, 2021) leading to severe COVID-19. Interestingly, the COVID-19 convalescent samples also showed the dysregulated crosstalk, further supporting a recent study where it has been shown that mild SARS-CoV-2 infection can leave an inflammatory imprint in the myeloid cells and can affect the macrophage effector functions (Bohnacker et al, 2022).…”

The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19

“… 85 In addition, a long-term inflammatory memory is imprinted on the monocyte/macrophage compartment driving aberrant effector functions and eicosanoid metabolism. 86 It is noteworthy that these imprints are related to increased levels of IL-1β, IL-6, and TNF secretion upon stimulation and are so far mainly observed in non-hospitalized patients with mild to moderate courses. This is in line with the observation that blood-derived monocytes from mild but not from severe patients secrete IL-1β and TNF.…”

Low-dose IL-2 reduces IL-21+T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients

“…The establishment of the Day 55 IL-2 signature is dose-dependent at Day 27, possibly reflecting a dose-dependent accumulation of injected IL-2 on the extracellular matrix within the interstitial space following subcutaneous dosing. A long-lasting immune alteration that also possibly reflects a continuing inflammatory stimulus or long-lived pro-inflammatory cytokines on the extracellular matrix has been reported in mild COVID-19 patients, with infection inducing a pro-inflammatory response in monocyte-derived macrophages that continues to be detected 3-5 months following SARS-CoV-2 infection 48 . In a separate study, pro-inflammatory markers such as IL-8 and sTIM-3 were still elevated four months after the cessation of COVID-19 symptoms in patients having had mild or moderate disease, but the increases resolved eight months post-infection except in patients with long COVID 49 .…”