Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Abstract

The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2; cytokine storm; multiple organ failure; renin-angiotensin system.

Fig. 1

The enzymatic cascade and the apelin/APJ axis in the renin-angiotensin system (RAS). Multiple biological effects of RAS are mediated by Ang2, Ang-(1-7), and apelin. Ang2 is a central regulator of the inflammatory response, mainly through AT1R. As a proinflammatory modulator, Ang2 interacts on both immune cells and tissue-resident cells. The activated synthesis of Ang2 from tissue-resident cells enhances vascular permeability by promoting the productions of proinflammatory factors including prostaglandins, VEGF, NFκB, TNFα, IL-1β, IL-6, and IFNγ via the activation of several pathways. Ang2 also recruits immune cells into the injury site(s) and enhances the inflammatory response by stimulating the production of cytokines/chemokines, resulting in fibrosis and tissue injury. ACE2 inactivates Ang2 into mainly Ang-(1-7), and thus the ACE2/Ang-(1-7)/MasR axis is the negative regulatory axis against the ACE/Ang2/AT1R axis in the RAS. Apelin antagonizes the ACE/Ang2/AT1R axis through negative feedback by ACE2 upregulation. In addition, the molecular interaction between AT1R and APJ suppresses the activity of AT1R. The activation of the ACE2/Ang-(1-7)/MasR axis and the apelin/APJ axis has shown an organoprotective effect. ACE, angiotensin-converting enzyme; Ang1, angiotensin 1; Ang2, angiotensin 2; AT1R, angiotensin 1 receptor; CHOP, CCAAT/enhancer-binding protein homologous protein; Cox-2, cyclooxygenase-2; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated kinase; GRP78, glucose-regulated protein 78; HDAC-1, histone deacetylase-1; IFNγ, interferon gamma; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IR-injury, ischemia reperfusion injury; JAK-STAT3, Janus kinase-signal transducer and activator of transcription system; JNK, C-jun-N-terminal kinase; MAPK, mitogen-activated protein kinase; MasR, Mas receptor; MCP-1, reactive oxygen species; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; PAH, pulmonary artery hypertension; PAI-1, plasminogen activator inhibitor-1; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; PKC, protein kinase C; ROS, reactive oxygen species; SOD, superoxide dismutase; TGFβ, transforming growth factor-beta; TNFα, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial cell growth factor.

Fig. 2

The therapeutics under clinical trials targeting the cytokine storm in SARS-CoV-2 infection. SARS-CoV-2 attaches to ACE2 and enters the host cell. Viral components are recognized by the MyD88 pathway in the endosome, leading to the releases of IL-6 and NFκB from immune cells including macrophages, monocytes, and dendrites. The possession of ACE2 by the virus causes the accumulation of Ang2 in the extracellular space. After the activation of AT1aR by excess Ang2 binding, sIL-6R is produced from the shedding of mIL-6R by ADAM10 and ADAM17 with a release of sTNFα from macrophages, mesenchymal stem cells (MSCs), and dendritic cells (DCs). IL-6 binds to the target cells via two signaling pathways: classic signaling only for specific immune cells, and trans-signaling for any cells including the immune cells, epithelial cells, and fibroblasts. In the classic signaling pathway, IL-6 binds to mIL-6R on the immune cells and activates B cells or differentiates CD8+ T cells, helper T cells, and Th17 cells, which triggers an anti-inflammation response. There is a negative feedback mechanism to the JAK-STAT pathway by SOCS3. In trans-signaling, IL-6/sIL-6R complex can bind to gp130 following the release of proinflammatory cytokines and IL-6 via three intracellular pathways without SOCS3 negative feedback. Since gp130 is highly expressed on almost all types of cells including the immune cells, sIL-6R shedding by ADAM17 provokes a surge of IL-surge mostly via trans-signaling. IL-6 stimulates the production of IL-6 and IL-17α from Th17 cells, resulting an IL-6 burst in its amplification cycle. The proinflammation cytokines increase vascular permeability and cell migration, enhancing the inflammation response. IL-6 also stimulates megakaryocytes, renal mesangial cells, and hepatocytes with the subsequent inflammatory response and vital organ injury. ARB/ACE-I, angiotensin receptor blocker/ACE2 inhibitor; AT1aR, angiotensin receptor subtype 1a; C3, complement component 3; E-cadherin, epithelial cadherin; gp130, glycoprotein 130; IL, interleukin; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; mIL-6R, membrane interleukin 6 receptor; MMP9, matrix metallopeptidase 9; MyD88, myeloid differentiation primary response 88; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFκB, nuclear factor kappa B; PI3K/Akt, phosphoinositide-3-kinase/protein Kinase B; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sIL-6R, soluble interleukin 6 receptor; SOCS3, the suppressor of cytokine signaling-3; STAT3, signal transducers and activators of transcription; sTNFα, soluble tumor necrosis factor alpha; Tfh, follicular helper T cell; Th0, naive T cell; Th17, T helper 17 cell; TMPRSS2, transmembrane protease serine 2; TNFα, tumor necrosis factor alpha; TPO, thrombopoietin; VEGF, vascular endothelial growth factor.

Fig. 3

The putative mechanisms of SARS-CoV-2 infection. SARS-CoV-2 has two surface proteins and single-strand RNA with nucleocapsid proteins. S1 protein binds to the host ACE2 by cleavage with TMPRSS2 and furin. After this attachment, the virus enters the host cell via fusion or endocytosis. In the endosome, cathepsins B and L activate the S2 protein of the virus for membrane fusion. The virus components are recognized by TLR7, leading to the release of proinflammation cytokines (IL-6, NFκB, VEGF, and MMP9) via the MyD88 pathway in immune cells such as macrophages, monocytes, and dendritic cells. Once the virus RNA is released in the host cytoplasm, the virus polypeptide chain with ribosome translation is processed in the replication/transcription complex by virus RNA polymerase. Replicated virus RNA and proteins are assembled and packed with the host membrane in the host cytoplasm. Virus is released from the cell by exocytosis or the host cell’s burst. ARB/ACE-I, angiotensin receptor blocker/ACE inhibitor; Cat L, cathepsin L; CatB, cathepsin B; IκB, inhibitory proteins of κB family; MMP9, matrix metallopeptidase 9; MyD88, myeloid differentiation primary response 88; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; rhACE2, recombinant human ACE2 protein; TLR7, Toll-like receptor 7; TMPRSS2, transmembrane protease serine 2.

Fig. 4

Clinical manifestations induced by SARS-CoV-2 infection. Organ dysfunction includes both direct cytotoxic effects of SARS-CoV-2 itself and cytokine-mediated damage. ACE2 was observed to be expressed in several types of tissue (including vessel endothelial and smooth muscle) and vital organs (lung, heart, intestine, brain, kidney, liver, etc.). The SARS-CoV-2 enters the host cells by binding to ACE2 and then directly damages the target organ. SARS-CoV-2 infection induces a release of proinflammatory cytokines (TNFα, IL-6 and others), resulting in injury to the target organ. ACS, acute coronary syndrome; ARDS, acute respiratory distress syndrome; BUN, blood urea nitrogen; CCL2, chemokine ligand 2; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; hsTnI, high sensitive troponin I; IFNγ, interferon gamma; KDSS, Kawasaki disease shock syndrome; MAS, macrophage activation syndrome; MCP-1, monocyte chemoattractant protein 1; NT-ProBNP, N-terminal-pro hormone B-type natriuretic peptide; PAH, pulmonary artery hypertension; PE, pulmonary embolism; TnT, troponin T; VTE, venous thromboembolism.