Researchers at the Indian Institute of Science Education and Research, Kolkata, India, in the group of Partho Sarothi Ray, have demonstrated that immune cells can sense cell density and “talk” to each other by regulating their function and their response to inflammatory stimuli. In a forthcoming research article in the Journal of Immunology, the researchers have shown that in a mechanism similar to quorum sensing in bacteria, mouse macrophages use the secreted protein Gelsolin (GSN) as a quorum sensing molecule to regulate their own functions in response to high cell density.
Quorum sensing is a well known mechanism in bacteria which initiates specific group behaviors only when a sufficient cell density has been reached and is mediated by specific diffusive molecule(s) called “autoinducers” that act as reporters for cell density. Quorum sensing is not known in multicellular organisms, but regulatory processes akin to quorum sensing mechanisms have recently been thought to play an important role in the mammalian immune system. Specifically, quorum sensing mechanisms appear to play an important role in determining monocyte/macrophage function and inflammation resolution. Macrophages are the first responders of the body to any infection or injury and initiate an immune response called inflammation. While inflammation is a protective response of the body, continued or aberrant inflammation causes tissue damage and is associated with many diseases such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, cancer and recently, COVID-19. Therefore, resolution of inflammation is an active and regulated process aimed at restoring tissue homeostasis and function. An outstanding question is whether a mechanism exists to sense when a sufficient number of immune cells have accumulated at a site of inflammation to initiate the resolution of inflammation.
The process of discovery began with a serendipitous observation by Reshma Sharma, the lead author of the study, that RAW264.7 mouse macrophage cells kept in culture without any treatment showed increased expression of a protein called programmed cell death 4 (PDCD4), a tumor suppressor protein. She went on to demonstrate that the increased expression of PDCD4 was a function of cell density and a secreted factor(s) in the cell culture medium caused the response. The same was observed in primary bone marrow derived macrophages. The team went on to discover that the factor was Gelsolin, a cytoplasmic protein known for its actin capping and scavenging activity. However, there is a secreted isoform of Gelsolin called plasma Gelsolin (pGSN) which is known to have anti-inflammatory functions. By a series of experiments, the researchers have shown that Gelsolin acts as the quorum sensing autoinducer, secreted by macrophages at high density, and which then acts on the surrounding cells to give rise to a quiescent, non-inflammatory macrophage phenotype. As part of these experiments, Binita Goswami, a co-author of the study, cloned, expressed, and purified human Gelsolin from bacteria at a high level of purity, and this recombinant human Gelsolin showed biological activity on macrophage cells similar to the plasma gelsolin secreted from macrophage cells.
This study has demonstrated a novel mechanism of action of Gelsolin, often referred to as a “master regulator of inflammation” that reinforces its role as a major player in the resolution of inflammation by being a sensor of immune cell density at the site of inflammation. What makes this more remarkable is that the analysis of immune based biomarkers in patients of COVID-19, in which the main cause of mortality is a hyperinflammatory response marked by a cytokine storm, has shown a correlation of decreased pGSN levels with disease severity and mortality. This has led to the proposition of recombinant human GSN as a potential therapeutic against COVID-19 and clinical trials are currently ongoing to test the efficacy of human GSN. The discovery of plasma GSN as a quorum sensor in macrophages provides new insights into its mode of function as a crucial regulator of macrophage activity in hyperinflammatory conditions and to the evolutionary conservation of quorum sensing mechanisms from bacteria to mammals.
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