Defects in the clearance of apoptotic cells are linked to inflammation and autoimmunity, and single nucleotide polymorphisms (SNPs) in the genes of several components of cell clearance pathways have been linked with rheumatoid arthritis (RA). However, investigations into one such cell clearance molecule, engulfment and cell motility protein 1 (ELMO1), have revealed an unexpected non-canonical role that questions conventional wisdom about conserved protein functions.

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“We initially hypothesized that loss of ELMO1 would worsen inflammatory arthritis, as ELMO1 promotes apoptotic cell engulfment,” explains corresponding author Kodi Ravichandran. “Surprisingly, Elmo1-deficient mice had reduced joint inflammation in two arthritis models.” Further investigations using conditional knockout mice and the K/B × N serum transfer model of arthritis revealed that it was the loss of ELMO1 function specifically in neutrophils that attenuated the development of arthritis.

A comparison of the protein interaction partners of ELMO1 in neutrophils and macrophages uncovered several neutrophil-specific interaction partners that had known associations with RA. Many of these proteins are involved in responses to inflammatory stimuli and cell migration, functions that were also restricted in Elmo1-deficient neutrophils. Knocking out total Elmo1 using an inducible system in mice with early, but not established, arthritis reduced disease severity compared with mice in which Elmo1 deletion was not induced, suggesting a role for ELMO1 in neutrophil recruitment during the early stages of arthritis.

“Neutrophils from the peripheral blood of human donors that carry an RA-associated SNP in ELMO1 had increased migratory capacity to chemokines linked to arthritis,” says lead author Sanja Arandjelovic. “These data suggest a neutrophil-specific ELMO1-dependent signalling nexus that could be a new target for therapeutic intervention in RA.”

the loss of ELMO1 function specifically in neutrophils … attenuated the development of arthritis

Given the interest in the potential to therapeutically target apoptotic pathways in RA, such cell type-specific, non-canonical functions of evolutionarily conserved components of cell clearance pathways seem to be deserving of further attention.