Apoptosis, a form of programmed cell death, can modulate various physiological processes including inflammation, the dysregulation of which can lead and/or contribute to various pathologies such as inflammatory arthritis. New findings show that during cell death, and while maintaining their membrane integrity, apoptotic cells can release metabolites that can influence the surrounding environment, including having anti-inflammatory effects.

“It has been a long standing observation in the field that apoptosis, unlike other forms of cell death, is anti-inflammatory, and can also have other beneficial effects such as inducing compensatory proliferation of cells in the tissue, as well as tissue repair,” explains corresponding author Kodi Ravichandran. “What has long been unknown is what makes the apoptotic process capable of these features.”

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Although previous studies had identified a number of apoptotic cell-derived soluble factors that function as ‘find-me’ signals to attract phagocytes, the full apoptotic secretome had yet to be characterized. In the new study, the researchers used a combination of metabolomics and transcriptomics to identify the factors released from apoptotic cells that might influence the surrounding tissue microenvironment. “We integrated data across different cell types and different modalities of cell death induction, using metabolic flux analysis, as well as a combination of in vitro and in vivo approaches and disease models, to comprehensively address the question of ‘how do apoptotic cells communicate with their neighbourhood’,” reports Ravichandran.

They identified a group of metabolites released from apoptotic cells that could induce specific gene expression programmes in healthy neighbouring phagocytic cells, including genes involved in cytoskeletal rearrangements, inflammation, wound healing or tissue repair, anti-apoptotic functions, metabolism and cell size regulation.

“By comparing the metabolites released from primary cells and cell lines with or without apoptotic stimuli, as well as characterizing the metabolites released via a specific membrane channel that gets activated during apoptosis (the pannexin 1 channel), we could narrow the list of metabolites down to six or even three with beneficial properties,” adds Christopher Medina, the first author of this work.

A cocktail of these three or six metabolites (termed Memix-3 or Memix-6, respectively) could alleviate inflammation and paw swelling in mice with K/BxN serum-induced arthritis. Notably, treatment with the Memix-3 cocktail could also protect the joints of the mice from inflammation, bone erosion and cartilage erosion.

“We hope these results advance the knowledge in the field in terms of considering metabolites, metabolism and cellular communication,” says Ravichandran. “Going forward, we are very interested in examining the mechanisms by which the apoptotic metabolites signal to the surrounding cells, as there is quite a bit we don’t know, such as what receptors are used by these metabolites, or whether the metabolites are passing through the membranes, and how they work jointly to produce their effects.”