Secretory leukoprotease inhibitor is required for efficient quercetin-mediated suppression of TNFα secretion

Abstract

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that in response to microbial infections generate long-lasting adaptive immune response. Following microbial uptake, DCs undergo a cascade of cellular differentiation that ultimately leads to “mature” DCs. Mature DCs produce a variety of inflammatory cytokines, including tumor necrosis factor-α (TNFα) a key cytokine for the inflammatory cascade. In numerous studies, polyphenols, including quercetin, demonstrated their ability to suppress TNFα secretion and protect from the onset of chronic inflammatory disorders. We show that murine bone marrow derived DCs express Slpi following quercetin exposure. Slpi is known to suppress LPS mediated NFκB activation, thus, it was hypothesized that its expression could be the key step for polyphenol induced inflammatory suppression. Slpi-KO DCs poorly respond to quercetin administration failing to reduce TNFα secretion in response to quercetin exposure. Supernatant from quercetin exposed DCs could also reduce LPS-mediated TNFα secretion by unrelated DCs, but this property is lost using an anti-Slpi antibody. In vivo, oral administration of quercetin is able to induce Slpi expression. Human biopsies from inflamed tract of the intestine reveal the presence of numerous SLPI+ cells and the expression level could be further increased by quercetin administration. We propose that quercetin induces Slpi expression that in turn reduces the inflammatory response. Our data encourages the development of nutritional strategies to improve the efficiency of current therapies for intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.

Secretory Leukoprotease Inhibitor (Slpi) Expression Is Required for Educating Murine Dendritic Cells Inflammatory Response Following Quercetin Exposure

“…Notably, LPS-induced IL-1β secretion from Slpi-KO DCs was increased following pre-exposure to quercetin ( Figure 1 ). Altogether, these analyses of the secretome confirm the role of quercetin as an anti-inflammatory agent [ 32 ], and provide a new insight into how quercetin can exert its effects on IL-1β secretion in the absence of Slpi. The anti-inflammatory effects of quercetin were absent or reduced in the absence of Slpi for all cytokines considered, with the exception of IL-1β, suggesting a different regulatory machinery involved in the secretion of this crucial inflammatory cytokine.…”

“…We recently demonstrated that quercetin-exposed DCs from wild-type (WT) mice reduce their ability to release tumor necrosis factor alpha (TNFα), interleukin 1 alpha, 1 beta, 6, 10 and 12 (IL-1α, IL-1β, IL-6, IL-10, and IL-12) following LPS administration [ 10 , 11 ] and that Slpi expression was a non-redundant checkpoint required for quercetin-mediated TNFα secretion suppression [ 32 ]. Here we explored the secretion of IL-1α, IL-1β, IL-6, IL-10, and IL-12 from quercetin-exposed Slpi-KO DCs following LPS administration.…”

“…We already demonstrated that quercetin was able to induce Slpi expression in murine colon if administered by gavage [ 32 ]. Quercetin is commonly present in fruits and vegetables; thus, we decided to evaluate whether Slpi expression could be induced by providing a quercetin-enriched diet to wild-type mice.…”

“…We already demonstrated that Slpi is required for quercetin-mediated immune suppression [ 32 ]. Quercetin exposure can induce Slpi expression even in the absence of inflammatory insult, but little is known about the inflammatory pathway regulated by Slpi.…”

Quercetin‐Induced miR‐369‐3p Suppresses Chronic Inflammatory Response Targeting C/EBP‐β

“…Furthermore, using whole‐genome microarray analysis, we showed that DCs exposed to quercetin after LPS activation demonstrated an altered molecular expression profile characterized by a reduced ability to present antigens and consequently initiate or maintain the adaptive immune response . Finally, even in the absence of LPS, we observed the induction of secretory leukoprotease inhibitor (Slpi) and the modulation of several iron metabolism genes all leading to inflammatory suppression and tissue repair pathways …”