Dataset Information

CITED2 restrains pro-inflammatory macrophage activation and response.

ABSTRACT: Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPAR?) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation in rosiglitazone-induced PPAR? activity, PPAR? recruitment to target gene promoters and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened pro-inflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1?) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1? in Cited2-deficient macrophages completely reversed elevated pro-inflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage pro-inflammatory activation and protect the host from inflammatory insults.

SUBMITTER: Kim GD

PROVIDER: S-EPMC5809687 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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CITED2 Restrains Proinflammatory Macrophage Activation and Response.

Kim Gun-Dong GD Das Riku R Rao Xiaoquan X Zhong Jixin J Deiuliis Jeffrey A JA Ramirez-Bergeron Diana L DL Rajagopalan Sanjay S Mahabeleshwar Ganapati H GH

Molecular and cellular biology 20180212 5

Macrophages are strategically distributed in mammalian tissues and play an essential role in priming the immune response. However, macrophages need to constantly strike a balance between activation and inhibition states to avoid a futile inflammatory reaction. Here, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage proinflammatory activation. Gain- and loss-of-function studies revealed ...[more]

PMID: 29203644

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Project description:Immune cells process a myriad of biochemical signals but their function and behavior are also determined by mechanical cues. Macrophages are no exception to this. Being present in all types of tissues, macrophages are exposed to environments of varying stiffness, which can be further altered under pathological conditions. While it is becoming increasingly clear that macrophages are mechanosensitive, it remains poorly understood how mechanical cues modulate their inflammatory response. Here we report that substrate stiffness influences the expression of pro-inflammatory genes and the formation of the NLRP3 inflammasome, leading to changes in the secreted protein levels of the cytokines IL-1β and IL-6. Using polyacrylamide hydrogels of tunable elastic moduli between 0.2 and 33.1 kPa, we found that bone marrow-derived macrophages adopted a less spread and rounder morphology on compliant compared to stiff substrates. Upon LPS priming, the expression levels of the gene encoding for TNF-α were higher on more compliant hydrogels. When additionally stimulating macrophages with the ionophore nigericin, we observed an enhanced formation of the NLRP3 inflammasome, increased levels of cell death, and higher secreted protein levels of IL-1β and IL-6 on compliant substrates. The upregulation of inflammasome formation on compliant substrates was not primarily attributed to the decreased cell spreading, since spatially confining cells on micropatterns led to a reduction of inflammasome-positive cells compared to well-spread cells. Finally, interfering with actomyosin contractility diminished the differences in inflammasome formation between compliant and stiff substrates. In summary, we show that substrate stiffness modulates the pro-inflammatory response of macrophages, that the NLRP3 inflammasome is one of the components affected by macrophage mechanosensing, and a role for actomyosin contractility in this mechanosensory response. Thus, our results contribute to a better understanding of how microenvironment stiffness affects macrophage behavior, which might be relevant in diseases where tissue stiffness is altered and might potentially provide a basis for new strategies to modulate inflammatory responses.

Dataset Information

CITED2 restrains pro-inflammatory macrophage activation and response.

Publications

CITED2 Restrains Proinflammatory Macrophage Activation and Response.

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