MK2/3 Are Pivotal for IL-33–Induced and Mast Cell–Dependent Leukocyte Recruitment and the Resulting Skin Inflammation

Abstract

The IL-1R family member IL-33R mediates Fcε-receptor-I (FcεRI)-independent activation of mast cells leading to NF-κB activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-α. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.

Mast cells initiate the vascular response to contact allergens by sensing cell stress

“…Confirming the in vivo findings, we found that MC stimulation with ATP in vitro resulted in prominent degranulation and histamine release but not in TNF production (Fig 2, I-K), whereas in contrast, IL-33 has been demonstrated to induce TNF production in vitro and MC degranulation in vivo but not in vitro. 7 Our data indicate that IL-33 signaling by MCs and amplification of stress responses by MC degranulation may be worth studying in more detail in the context of human inflammatory skin diseases. The observed mechanisms should have an impact on therapeutic decisions in cases of contact sensitivity which may be difficult to manage.…”

Non‐IgE mediated mast cell activation

“…IL‐33 can serve as a potent activator of MCs and has been reported to promote survival, maturation, migration, adhesion, and the production of several pro‐inflammatory cytokines (eg, IL‐4, IL‐5, IL‐6, IL‐8, and IL‐13) and chemokines (eg, MIP‐1α and MCP‐1) in these cells . In addition, in the presence of SCF, IL‐33 can also induce TNF production in MCs via a MK2/3‐, ERK1/2‐, and PI3K‐dependent pathway . Recently, Taracanova et al have shown that IL‐33 and SP together amplify TNF secretion from MCs, which is mediated by the interaction of NK‐1R and ST2 receptors .…”

“…[250][251][252][253][254][255][256][257][258][259][260] In addition, in the presence of SCF, IL-33 can also induce TNF production in MCs via a MK2/3-, ERK1/2-, and PI3K-dependent pathway. 261 Recently, Taracanova et al have shown that IL-33 and SP together amplify TNF secretion from MCs, which is mediated by the interaction of NK-1R and ST2 receptors. 262 In addition, IL-33 and…”

IL‐33‐activated murine mast cells control the dichotomy between RORγt+ and Helios+Tregs via the MK2/3‐mediated IL‐6 production in vitro

“…The effector functions of the IL‐33R depend on the IL‐1 associated protein (IL‐1Racp) and can be modulated by c‐Kit activation in mast cells . Furthermore, IL‐33 via IL‐33R induces the MyD88‐TAK1‐IKK2‐dependent activation of NF‐κB and the activation of the p38‐MK2/3 signaling axis in mast cells . Thereby, MK2/3 mediates the IL‐33‐induced signaling via the PI3K‐PKB/Akt‐mTOR‐ribosomal S6 kinases (RSKs) pathway and stabilizes the mRNAs of IL‐6 and TNFα .…”