Inhibition of ERK MAPK Suppresses IL-23- and IL-1-Driven IL-17 Production and Attenuates Autoimmune Disease

Abstract

IL-17-producing CD4+ T (Th17) cells are pathogenic in many autoimmune diseases. The induction and expansion of Th17 cells is directed by cytokines, including IL-23 and IL-1β, produced by innate immune cells through activation of pathogen recognition receptors. The NF-κB and IFN regulatory factor families of transcriptional factors mediate IL-12 production; however, distinct signaling pathways appear to be required for IL-23 production. In this study, we show that inhibition of ERK MAPK suppressed IL-23 and IL-1β production by dendritic cells stimulated with TLR or dectin-1 agonists but did not affect IL-12p70 production. Furthermore, an ERK inhibitor suppressed the ability of Ag-pulsed TLR-activated dendritic cells to induce Ag-specific Th17 cells in vivo, but interestingly also inhibited the induction of Th1 cells. Treatment with an ERK inhibitor attenuated experimental autoimmune encephalomyelitis (EAE), when administered either at the induction phase of acute EAE or during remission in the relapsing-remitting EAE model. This was associated with significant suppression of autoantigen-specific Th17 and Th1 responses. The suppressive effect of the ERK inhibitor on attenuation of EAE was reversed by administration of IL-1β and IL-23. Our findings suggest that ERK MAPK plays a critical and hitherto undescribed role in activating innate production of IL-23 and IL-1β, which promote pathogenic T cell responses, and therefore represents an important target for therapeutic intervention against autoimmune diseases.

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…This is consistent with a previous report showing that ERK is responsible for augmented Th17 responses induced by LPStreated DCs (53). Nevertheless, the roles of ERK signaling in the regulation of Th17 development have become controversial.…”

Escherichia coliHeat-Labile Enterotoxin Promotes Protective Th17 Responses against Infection by Driving Innate IL-1 and IL-23 Production

“…In addition to the role of IL-1b, our results suggest that induction of IL-1a and IL-23 is also involved in the adjuvant function of LT. IL-1a, like IL-1b, can synergize with IL-23 to promote IL-17 production by T cells but does not require processing by caspase-1. We have previously reported that activation of ERK MAPK signaling plays a role in TLR-induced IL-23 and IL-1b production and subsequent Th17 cell differentiation (28). In the present study, we found that both LT and LTK63 induced sustained activation of ERK in DCs and that inhibition of ERK suppressed LT-and LTK63-induced IL-23p19 mRNA, as well as IL-23 and IL-1a protein production by LPS-primed DCs.…”

“…A number of studies have demonstrated that components of the MAPK pathway play a major part in the regulation of DCs and macrophages that promote Th1/Th2 cell differentiation (24)(25)(26). In particular, the MAPK ERK pathway has been shown to have an important function in regulating IL-12 production (27) and in mediating TLRinduced IL-23 production by DCs (28).…”

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

“…The implication of ERK downstream of collagen in IL-17 production is supported by studies showing that MAPK/ERK inhibitors inhibited Th17 development and attenuated colitis (36) and experimental autoimmune encephalomyelitis (37). The PI3K/AKT pathway has been associated with Th17 cell development (38) and with IL-17 expression by CCR6 + human memory T cells (39).…”