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Stress hormone signaling through β-adrenergic receptors regulates macrophage mechanotype and function.

ABSTRACT: Critical functions of immune cells require them to rapidly change their shape and generate forces in response to cues from their surrounding environment. However, little is known about how soluble factors that may be present in the microenvironment modulate key aspects of cellular mechanobiology-such as immune cell deformability and force generation-to impact functions such as phagocytosis and migration. Here we show that signaling by soluble stress hormones through β-adrenoceptors (β-AR) reduces the deformability of macrophages; this is dependent on changes in the organization of the actin cytoskeleton and is associated with functional changes in phagocytosis and migration. Pharmacologic interventions reveal that the impact of β-AR signaling on macrophage deformability is dependent on actin-related proteins 2/3, indicating that stress hormone signaling through β-AR shifts actin organization to favor branched structures rather than linear unbranched actin filaments. These findings show that through remodeling of the actin cytoskeleton, β-AR-mediated stress hormone signaling modulates macrophage mechanotype to impact functions that play a critical role in immune response.-Kim, T.-H., Ly, C., Christodoulides, A., Nowell, C. J., Gunning, P. W., Sloan, E. K., Rowat, A. C. Stress hormone signaling through β-adrenergic receptors regulates macrophage mechanotype and function.

SUBMITTER: Kim TH

PROVIDER: S-EPMC6404566 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Stress hormone signaling through β-adrenergic receptors regulates macrophage mechanotype and function.

Kim Tae-Hyung TH Ly Chau C Christodoulides Alexei A Nowell Cameron J CJ Gunning Peter W PW Sloan Erica K EK Rowat Amy C AC

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20181203 3

Critical functions of immune cells require them to rapidly change their shape and generate forces in response to cues from their surrounding environment. However, little is known about how soluble factors that may be present in the microenvironment modulate key aspects of cellular mechanobiology-such as immune cell deformability and force generation-to impact functions such as phagocytosis and migration. Here we show that signaling by soluble stress hormones through β-adrenoceptors (β-AR) reduce ...[more]

PMID: 30509116

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Project description:RationaleMicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize β-adrenergic receptor (βAR) signaling, β-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the β-arrestin-biased βAR ligand carvedilol, we previously showed that β-arrestin1 (not β-arrestin2)-biased β1AR (not β2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes β-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1.ObjectiveHere, we investigate whether β-arrestin-mediated βAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling.Methods and resultsIn mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a β-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2ARs and β1ARs, respectively. Mechanistically, β-arrestin 1 or 2 regulates maturation of three newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of β-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, β-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets.ConclusionsOur findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

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Stress hormone signaling through β-adrenergic receptors regulates macrophage mechanotype and function.

Publications

Stress hormone signaling through β-adrenergic receptors regulates macrophage mechanotype and function.

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