ABSTRACT
The importance of the complement component C1q has been highlighted by its involvement in autoimmunity, infection, inflammatory diseases, and tumors. The unique tulip-like structure of C1q has both a collagen-like stalk (C1q tail) and heterotrimeric globular head (gC1q), each with different binding specificities, and the binding of these components to their respective receptors leads to functional complexities in the body and bridges innate and adaptive immunity. This review describes the fundamental roles of C1q in various microenvironments and focuses on the importance of the interactions of C1q and its receptors with the inhibitory receptor LAIR-1 in maintaining homeostasis. Current therapeutic opportunities modulating LAIR-1 are also discussed. Immunology: complement protein in health and disease Research into the activities of the protein C1q, involved in a cascade of molecular interactions of the immune response called complement activation, is revealing new details of the protein’s role and opening up possible new therapeutic opportunities. Myoungsun Son at Feinstein Institutes for Medical Research in Manhasset, USA, reviews the involvement of C1q in infection, autoimmunity, inflammatory diseases and tumors. The interaction of C1q with a receptor protein called LAIR-1 seems to be particularly significant. LAIR-1 is present in the membrane of most blood-forming cells and is involved in maintaining the healthy balance of cellular activities referred to as homeostasis. Emerging research suggests that targeting the interactions between C1q and LAIR-1 could enable the development of new treatments for many diseases, including inflammatory diseases, the autoimmune condition lupus, a variety of cancers, and possibly Covid-19.
ABSTRACT
Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1ß, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.