The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis

Abstract

Dendritic cell (DC)–mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/β secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α–mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.

MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis

“…Our in vitro experiments however, in both murine and human systems, demonstrated a clear role of MK2 in broad macrophage biology, including polarization into M2 macrophages and macrophage production of proangiogenic factors, consistent with the proposed mechanism for the observed mouse phenotypes. A functional role for MK2 in other myeloid cell types, including neutrophils and dendritic cells (39)(40)(41), could also contribute to the observed phenotype.…”

An Angle on MK2 Inhibition—Optimization and Evaluation of Prevention of Activation Inhibitors

“…Therefore, sequestration of p38 cannot be the only explanation for this, ando ur data contradict previous literature reports. [2] More recent scientific reports [25][26][27][28][29][30][31] demonstrate that IL-10 is directly regulated by MK2 in addition to MSK1. As such, our data invalidate MK2 as at arget for selective inhibition of inflammation.…”

Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response

“…Roberts et al found that PI3k activated by CR3 ligation led to the upregulation of MKP-1, which can inhibit p38 MAPK and thereby suppress the inflammatory response [173]. Soukup et al described that a similar effect was mediated by MK2, which could inhibit TLR-mediated inflammatory responses triggered by LPS [154]. None of these factors appear to be significantly affected in our transcriptomic studies, but their involvement cannot be excluded as upregulation of these factors is transient.…”

“…None of these factors appear to be significantly affected in our transcriptomic studies, but their involvement cannot be excluded as upregulation of these factors is transient. Soukup et al measured MK2 expression at 6h, 12h, 24h and 48h, but could only detect upregulation at 24h [154]. As previously mentioned, a setting where p38 MAPK and NFkβ signaling is stronger leads to an inflammatory response, whereas if PI3K/AKT and ERK dominate, inflammation is dampened [146].…”

“…In addition, an upregulation of gene expression of MyD88, a signal transducer directly downstream of TLR8, was observed. T cells primed by C-HIV-exposed dendritic cells… responses in dendritic cells [154]. In addition, ERK, JNK and p38 MAPK are required for dendritic cell maturation: either directly or via interferon signaling depending on the exact setting [155].…”