TY - JOUR
T1 - Endogenous secretory leukocyte protease inhibitor inhibits microbial-induced monocyte activation
AU - Nugteren, Sandrine
AU - Simons-Oosterhuis, Ytje
AU - Menckeberg, Celia L.
AU - Hulleman-van Haaften, Danielle H.
AU - Lindenbergh-Kortleve, Dicky J.
AU - Samsom, Janneke N.
N1 - Publisher Copyright:
© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.
PY - 2023/2
Y1 - 2023/2
N2 - In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF-κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation. We questioned whether monocytes can produce SLPI and whether endogenous SLPI can inhibit monocyte activation. We demonstrate that human THP-1 monocytic cells produce SLPI and that CD68+ SLPI-producing cells can be detected in human intestinal lamina propria. Knockdown of SLPI in human THP-1 cells significantly increased NF-κB activation and subsequent C-X-C motif chemokine ligand 8 (CXCL8) and TNF-α production in response to microbial stimulation. Reconstitution of SLPI-deficient cells with either full-length SLPI or SLPI lacking its signal peptide rescued inhibition of NF-κB activation and cytokine production, demonstrating that endogenous SLPI inhibits monocytic cell activation. Unexpectedly, exogenous SLPI did not inhibit CXCL8 or TNF-α production, despite efficient uptake. Our data argue that endogenous SLPI can regulate the threshold of activation in monocytes, thereby preventing activation by commensal bacteria in mucosal tissues.
AB - In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF-κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation. We questioned whether monocytes can produce SLPI and whether endogenous SLPI can inhibit monocyte activation. We demonstrate that human THP-1 monocytic cells produce SLPI and that CD68+ SLPI-producing cells can be detected in human intestinal lamina propria. Knockdown of SLPI in human THP-1 cells significantly increased NF-κB activation and subsequent C-X-C motif chemokine ligand 8 (CXCL8) and TNF-α production in response to microbial stimulation. Reconstitution of SLPI-deficient cells with either full-length SLPI or SLPI lacking its signal peptide rescued inhibition of NF-κB activation and cytokine production, demonstrating that endogenous SLPI inhibits monocytic cell activation. Unexpectedly, exogenous SLPI did not inhibit CXCL8 or TNF-α production, despite efficient uptake. Our data argue that endogenous SLPI can regulate the threshold of activation in monocytes, thereby preventing activation by commensal bacteria in mucosal tissues.
UR - http://www.scopus.com/inward/record.url?scp=85145090884&partnerID=8YFLogxK
U2 - 10.1002/eji.202249964
DO - 10.1002/eji.202249964
M3 - Article
C2 - 36480463
AN - SCOPUS:85145090884
SN - 0014-2980
VL - 53
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 2
M1 - 2249964
ER -