Fig. 2.

(R) Potential mechanisms of inflammatory responses caused by SARS-CoV-2. Based on recent investigations on SARS-CoV, the inflammatory responses in COVID-19 were divided into primary and secondary responses. Primary inflammatory responses exist early after viral infection, before the arrival of neutralizing antibodies (NAb). These responses are primarily led by active viral replication, viral-induced ACE2 downregulation and shedding, and host antiviral responses. Secondary inflammatory responses commence with the production of adaptive immunity and NAb. The virus–NAb complex can also cause FcR-mediated inflammatory responses; (S) antibody-dependent enhancement (ADE) of viral infection and inflammatory responses mediated by Fc receptor. A, ADE exists when antiviral NAb cannot completely neutralize the virus. Rather, the virus–NAb complex adheres to the Fc receptor (FcR), resulting in viral endocytosis and infection of the target cells. B, Binding of virus–NAb complex to FcR can also stimulate proinflammatory signalling, altering macrophage responses to the growth of proinflammatory (M1 or classically activated) macrophages in lungs. The M1 macrophages secrete inflammatory cytokines including IL-8 and MCP-1, resulting in lung injury. C, Possible therapeutics based on targeting the Fc receptors to prevent SARS-CoV-2-mediated inflammatory responses. From left to right, FcR can be blocked by employing anti-Fc specific antibodies, intravenous immunoglobulin (IVIG) or small molecules. The inhibitory FcR, FccRIIB, may also be selected to inhibit FcR activation. Reprinted with permission from Ref. [54]. Copyright 2020 Springer Nature