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

Author:

von Beek ChristopherORCID,Fahlgren Anna,Geiser PetraORCID,Di Martino Maria LetiziaORCID,Lindahl OttoORCID,Prensa Grisna I.ORCID,Mendez-Enriquez ErikaORCID,Eriksson JensORCID,Hallgren JennyORCID,Fällman MariaORCID,Pejler Gunnar,Sellin Mikael E.ORCID

Abstract

AbstractMast 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.

Funder

Knut och Alice Wallenbergs Stiftelse

Vetenskapsrådet

Science for Life Laboratory

Malin and Lennart Philipson Foundation (MOLPS) - LP Award

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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