Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells

Abstract

Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is expressed in basophils and eosinophils but in not in mast cells. SLPI-deficient (Slpi−/−) basophils produce more cytokines than wild-type mice after IgE stimulation. Although the deletion of SLPI in basophils did not affect the release of chemical mediators upon IgE stimulation, the enzymatic activity of the serine protease tryptase was increased in Slpi−/− basophils. Mice transferred with Slpi−/− basophils were highly sensitive to IgE-mediated chronic allergic inflammation. Eosinophils lacking SLPI showed greater interleukin-6 secretion and invasive activity upon lipopolysaccharide stimulation, and the expression of matrix metalloproteinase-9 by these eosinophils was increased without stimulation. The absence of SLPI increases JNK1 phosphorylation at the steady state, and augments the serine phosphorylation of JNK1-downstream ETS transcriptional factor Elk-1 in eosinophils upon stimulation. Of note, SLPI interacts with a scaffold protein, JNK-interacting protein 3 (JIP3), that constitutively binds to the cytoplasmic domain of toll-like receptor (TLR) 4, suggesting that SLPI controls Elk-1 activation via binding to JIP3 in eosinophils. Mice transferred with Slpi−/− eosinophils showed the exacerbation of chitin-induced allergic inflammation. These findings showed that SLPI is a negative regulator in allergic effector cells and suggested a novel inhibitory role of SLPI in the TLR4 signaling pathways.

Secretory Leukocyte Protease Inhibitor Is Present in Circulating and Tissue-Recruited Human Eosinophils and Regulates Their Migratory Function

“…Elevated levels of both eosinophils and SLPI in tissues affected by allergy-associated inflammatory diseases suggest that eosinophils may be a source and/or target of SLPI. This is in line with a recent study that demonstrated that SLPI is expressed in mouse eosinophils and that the ability of SLPI-deficient murine eosinophils to secrete IL-6 and express metalloproteinase-9 (MMP-9) is diminished ( 13 ). However, SLPI expression and/or function in human eosinophils remain unknown.…”

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation

“…SLPI is known to have the ability to directly penetrate cells to inhibit nuclear factor κB (NF-κB) signaling ( Taggart et al, 2005 ), and exogenously administered SLPI ( Wright et al, 1999 ), as well as SLPI expressed from a transgene ( Marino et al, 2011 ; Raundhal et al, 2015 ), reduces eosinophilic inflammation in models of AAI. Additionally, SLPI has been demonstrated to be an endogenous regulator of eosinophil and basophil function by inhibiting Toll-like receptor 4 (TLR4) signaling in allergic inflammation ( Matsuba et al, 2017 ). However, more studies investigating the tissue-specific effects of SLPI resulting from airway bacterial colonization will be needed to address which cell types and molecular targets are affected by SLPI and mediate protection from AAI.…”

Neutrophils and Activated Macrophages Control Mucosal Immunity by Proteolytic Cleavage of Antileukoproteinase

“…These anti-inflammatory mechanisms likely form the basis of positive outcomes observed for treatment with SLPI in animal models for inflammatory diseases such as arthritis ( 11 , 12 ) and healing of chronic wounds ( 6 , 13 ). In addition, genetic deletion of SLPI in eosinophils and basophils results in increased allergic inflammation ( 14 ).…”

“…We recently discovered the slpi gene to be one of the only three genes significantly altered in MMP-9 KO mice compared to WT mice ( 32 ). In addition, others found that SLPI-deficient eosinophils have increased MMP-9 gene transcription ( 14 ). These and other studies point toward reciprocal regulation of SLPI and MMP-9 and impose to further investigate a possible link between MMP-9 and SLPI.…”