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Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-?B activation.

ABSTRACT: Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-?B signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-?B activation occurs through a blockade in transforming growth factor ?-activated kinase 1 (TAK1) and IKK? activation. As a consequence, NF-?B (p65) phosphorylation is reduced, its translocation to the nucleus is inhibited and NF-?B-mediated inflammatory cytokine transcription is suppressed. Gene Set Enrichment Analysis reveals that this suppression of NF-?B activation is not restricted to post-translational modifications of the canonical NF-?B pathway, but is also imprinted at the transcriptional level. Thus neutrophils exert a sustained anti-inflammatory phenotypic reprogramming of the macrophage, which is reflected by the sustained reduction in the release of pro- but not anti- inflammatory cytokines from the macrophage. Together, our findings identify a novel apoptosis-independent mechanism by which neutrophils regulate the mediator profile and reprogramming of monocytes/macrophages, representing an important nodal point for inflammatory control.

SUBMITTER: Marwick JA

PROVIDER: S-EPMC5986789 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation.

Marwick John A JA Mills Ross R Kay Oliver O Michail Kyriakos K Stephen Jillian J Rossi Adriano G AG Dransfield Ian I Hirani Nikhil N

Cell death & disease 20180604 6

Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-κB signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-κB activation occurs through a blockade in transforming growth factor β-activated kinase 1 (TAK1) and IKKβ activation. As a consequence, NF-κB (p65) phosphorylation is reduced, its translocatio ...[more]

PMID: 29867198

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Project description:BackgroundTo investigate the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium during osteoarthritis (OA) development.MethodsTen-week-old male C57BL/6 mice were randomized and assigned to vehicle, collagenase-induced OA (CIOA), or CIOA with intra-articular fargesin treatment groups. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International (OARSI) score. Immunostaining and western blot analyses were conducted to detect relative protein. Raw264.7 cells were treated with LPS or IL-4 to investigate the role of polarized macrophages. ADTC5 cells were treated with IL-1β and conditioned medium was collected to investigate the crosstalk between chondrocytes and macrophages.ResultsFargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by downregulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Conditioned medium (CM) from M1 macrophages treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, and type X collagen and increased Col2a1 and SOX9 in OA chondrocytes, but fargesin alone did not affect chondrocyte catabolic processes. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling.ConclusionsThis study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by downregulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.

Dataset Information

Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-?B activation.

Publications

Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation.

Similar Datasets

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