IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Abstract

Mast cells contain large amounts of fully active proteases that are stored in complex with serglycin proteoglycan in their secretory granules. Upon degranulation, such serglycin:protease complexes are released to the extracellular space and can potentially have an impact on the local inflammatory reaction, either through direct effects of serglycin proteoglycan or through effects mediated by its bound proteases. The objective of this study was to address this scenario by investigating the possibility that serglycin‐associated proteases can regulate levels of pro‐inflammatory cytokines. Indeed, we show here that activated cultured peritoneal mast cells from wild type mice efficiently reduced the levels of exogenously administered IL‐6 and IL‐17A, whereas serglycin‐deficient mast cells lacked this ability. Furthermore, our data suggest that the reduction of IL‐6 and IL‐17A concentrations is due to proteolytic degradation mediated by serglycin‐dependent serine proteases. Moreover, we show that activated mast cells have the capacity to release IL‐6 and that the levels of this cytokine in supernatants were markedly higher in cultures of serglycin‐deficient versus serglycin‐sufficient mast cells, suggesting that serglycin‐dependent serine proteases also participate in the regulation of endogenously produced IL‐6. In summary, although the general consensus is that mast cells have a pathogenic impact on inflammatory settings, this study identifies a role for a mast cell‐derived serglycin:serine protease axis in down‐regulating levels of major inflammatory cytokines. These findings support the notion that mast cells could have a dual role in inflammatory settings, by both being able to secrete pathogenic compounds and being able to regulate their levels after release.

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

“…5B). This protein is involved in regulating the half-life of cytokines and apoptosis induction (46); the downregulation of this protein may thus also contribute to pathophysiological processes resulting in tumor escalation. Other proteins such as platelet endothelial cell adhesion molecule (PECAM1) and platelet glycoprotein 4 (CD36) were detected with similar levels in all platelets, dem- onstrating that differential regulation was only affecting a few selected proteins.…”

Serglycin-Deficiency Causes Reduced Weight Gain and Changed Intestinal Cytokine Responses in Mice Infected With Giardia intestinalis

“…The pro-inflammatory cytokine IL-6 has been shown to play a significant role in the host control of Giardia infections ( 32 ) and in addition SG-dependent serine-proteases have been shown to be involved in the degradation of IL-6 ( 33 ). With this in mind the serum IL-6 levels was determined with ELISA in the two independent experimental infections [experiment #1 (SG +/+ n = 6, SG −/− n = 6) and #2 (SG +/+ n = 5, SG −/− n = 11)].…”

Degradation of Monocyte Chemoattractant Protein-1 by Tryptase Co-Released in Immunoglobulin E-Dependent Activation of Primary Human Cultured Mast Cells

“…Several reports have shown that mast cell serine proteases can proteolytically activate cytokines and chemokines [20][21][22][23][24]. On the other hand, a recent report demonstrated that activated cultured mouse peritoneal mast cells can regulate levels of IL-3, IL-6, IL-13, IL-17A, and eotaxin by releasing serglycin-dependent serine proteases, which mediate the proteolytic degradation of these cytokines and chemokines [25]. Previous in vitro studies with purified human skin-derived mast cells have shown that chymase and cathepsin G released upon FcεRI cross-linking degrade cytokines, such as IL-6 and IL-13, that are co-released from these activated mast cells [7].…”