Toll-Like Receptor 2-Tpl2-Dependent ERK Signaling Drives Inverse Interleukin 12 Regulation in Dendritic Cells and Macrophages.

ABSTRACT: This study investigated responses to Toll-like receptor 2 (TLR2)-driven extracellular signal-related kinase (ERK) signaling in dendritic cells (DCs) versus macrophages. TLR2 signaling was induced with Pam₃Cys-Ser-Lys₄, and the role of ERK signaling was interrogated pharmacologically with MEK1/2 inhibitor U0126 or genetically with bone marrow-derived macrophages or DCs from Tpl2^-/- mice. We assessed cytokine production via enzyme-linked immunosorbent assay (ELISA) or V-Plex, and mRNA levels were assessed via reverse transcriptase quantitative PCR (qRT-PCR). In macrophages, blockade of ERK signaling by pharmacologic or genetic approaches inhibited interleukin 10 (IL-10) expression and increased expression of the p40 subunit shared by IL-12 and IL-23 (IL-12/23p40). In DCs, blockade of ERK signaling similarly inhibited IL-10 expression but decreased IL-12/23p40 expression, which is opposite to the effect of ERK signaling blockade on IL-12/23p40 in macrophages. This difference in IL-12/23p40 regulation correlated with the differential expression of transcription factors cFos and IRF1, which are known to regulate IL-12 family members, including IL-12 and IL-23. Thus, the impact of ERK signaling in response to TLR2 stimulation differs between macrophages and DCs, potentially regulating their distinctive functions in the immune system. ERK-mediated suppression of IL-12/23p40 in macrophages may prevent excessive inflammation and associated tissue damage following TLR2-stimulation, while ERK-mediated induction of IL-12/23p40 in DCs may promote priming of T helper 1 (Th1) responses. A greater understanding of the role that ERK signaling plays in different immune cell types may inform the development of host-directed therapy and optimal adjuvanticity for a number of infectious pathogens.

SUBMITTER: Groft SG 

PROVIDER: S-EPMC7927937 | biostudies-literature |

REPOSITORIES: biostudies-literature