Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation

Abstract

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α–dependent microRNA (miR)–210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210–based therapeutic and diagnostic strategies.

Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

“…Beyond pure hypoxic exposure alone, an appreciation is advancing of the mechanistic connections of ISCU specifically with IL-6 ( 41 ), suggesting the importance of hypoxia and IL-6 together in controlling ISCU-dependent pathophenotypes. Thus, in PAECs exposed to a combination of recombinant IL-6/soluble IL-6 receptor (sIL-6R) and hypoxia, BRD2889 reversed the increase in GSTP1 activity and reversed the decrease in ISCU expression (fig.…”

IL-13 Derived Type 2 Innate Lymphocytes Ameliorates Cardiomyocyte Apoptosis Through STAT3 Signaling Pathway

“…During sepsis, activation of type 1 immune response leads to the release of abundant cytokines, which is recognized as the common feature of sepsis, known as "cytokine storm" (Virga et al, 2021). Intriguingly, activation of anti-inflammatory type 2 immune response can antagonize proinflammatory type 1 immunity (Verhoef et al, 2019).…”

“…Protein extraction and Western blotting were performed as previously described (Virga et al, 2021). Briefly, the protein sample (30 µg) was electrophoresed in SDS-PAGE and transferred to the PVDF membrane.…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…Similarly, HIF-1α is upregulated in SARS-CoV-2 patients and promotes macrophage inflammatory responses ( Zhu et al, 2021a ). HIF-1α can also induce miR-210 to shift macrophages to a proinflammatory state while knocking down miR-210 limits the cytokine storm ( Virga et al, 2021 ). Nevertheless, the complex formation between HIF-1α and PKM2 inhibits the expression of HIF-1α and IL-1β and promotes the expression of IL-10, in turn leading to a shift in the macrophage phenotype from proinflammatory M1 to pro-reparatory M2 ( Palsson-McDermott et al, 2015 ).…”

“…In addition, it was shown by using galactose medium and 2-DG that inhibition of glycolysis can repress HCV from cell to supernatant release ( Yu et al, 2021 ). While glycolysis may contribute to the inflammatory storm ( Wang et al, 2020b ; Virga et al, 2021 ), the absence of glycolysis can lead to the loss of antiviral function in NK cells. Sheppard et al (2021) found that LDHA-mediated aerobic glycolysis is a hallmark of NK cell activation.…”