A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection

Abstract

Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.

New Insight into Intestinal Mast Cells Revealed by Single-Cell RNA Sequencing

“…Mature MCs are tissue-resident innate immune cells that are present in all organs, particularly in skin, lung, and intestinal mucosa, and are distributed close to blood and lymphatic vessels and nerves. Thanks to their strategical localization and to the expression of a wide array of receptors, mature MCs act as tissue sentinels, able to firstly detect the presence of bacteria and parasites and to respond to different microenvironmental stimuli [ 4 , 5 , 6 , 7 ].…”