Weathering the Storm: Harnessing the Resolution of Inflammation to Limit COVID-19 Pathogenesis

Abstract

The resolution of inflammation is a temporally and spatially coordinated process that in its innate manifestations, primarily involves neutrophils and macrophages. The shutdown of infection or injury-induced acute inflammation requires termination of neutrophil accumulation within the affected sites, neutrophil demise, and clearance by phagocytes (efferocytosis), such as tissue-resident and monocyte-derived macrophages. This must be followed by macrophage reprogramming from the inflammatory to reparative and consequently resolution-promoting phenotypes and the production of resolution-promoting lipid and protein mediators that limit responses in various cell types and promote tissue repair and return to homeostatic architecture and function. Recent studies suggest that these events, and macrophage reprogramming to pro-resolving phenotypes in particular, are not only important in the acute setting, but might be paramount in limiting chronic inflammation, autoimmunity, and various uncontrolled cytokine-driven pathologies. The SARS-CoV-2 (COVID-19) pandemic has caused a worldwide health and economic crisis. Severe COVID-19 cases that lead to high morbidity are tightly associated with an exuberant cytokine storm that seems to trigger shock-like pathologies, leading to vascular and multiorgan failures. In other cases, the cytokine storm can lead to diffuse alveolar damage that results in acute respiratory distress syndrome (ARDS) and lung failure. Here, we address recent advances on effectors in the resolution of inflammation and discuss how pro-resolution mechanisms with particular emphasis on macrophage reprogramming, might be harnessed to limit the universal COVID-19 health threat.

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

“…The SARS-CoV2 hyper-inflammatory syndrome ( 129 ) could result from the absence of macrophage reprogramming after efferocytosis of SARS-CoV2-infected dying cells. Severe SARS-CoV2 infections may therefore be considered as another disease resulting from non-resolving inflammation ( 1 ), and could be treated with resolution therapy (as recently proposed ( 130 )). SuperMApo constitutes a new pro-resolving complex biological drug candidate in the therapeutic arsenal of resolution therapy.…”

Glucocorticoids and COVID-19

“…GCs play a significant role in targeting the anti-inflammatory mechanisms, as according to the Randomized Evaluation of COVID-19 Therapy (RECOVERY) clinical trial GCs and specifically dexamethasone are able to regulate satiated or CD11 blow macrophages. The anti-inflammatory factors IL-10, PGE2, and platelet-activating factor (PAF) are increased by pro-resolving macrophages [19] , [133] , [134] . Interestingly, with or without transcriptional mechanisms, the GCs result in decreased expression of genes implicated in inflammatory pathways, like in TLR7 signaling in B-cells, decreased antigen presentation in DCs, elevation of IL-10 levels and decrease of inflammation inducing factors, such as IL-6, TNF-α and PGE2 [134] , [135] .…”

“…The anti-inflammatory factors IL-10, PGE2, and platelet-activating factor (PAF) are increased by pro-resolving macrophages [19] , [133] , [134] . Interestingly, with or without transcriptional mechanisms, the GCs result in decreased expression of genes implicated in inflammatory pathways, like in TLR7 signaling in B-cells, decreased antigen presentation in DCs, elevation of IL-10 levels and decrease of inflammation inducing factors, such as IL-6, TNF-α and PGE2 [134] , [135] .…”

Antimicrobial peptides: Defending the mucosal epithelial barrier

“…Calprotectin heterotetramers also lose DAMP activity because this multimer shows reduced access to the TLR4/MD2-binding site, which mitigates a broader inflammatory response [ 199 ]. By reducing the inflammatory response, off-target tissue damage is minimized during clearance of the infection [ 200 – 203 ].…”