Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice

Fujisaka, Shiho; Usui, Isao; Ikutani, Masashi; Aminuddin, Aminuddin; Takikawa, Akiko; Tsuneyama, Koichi; Mahmood, Amjad; Goda, Nobuhito; Nagai, Yoshinori; Takatsu, Kiyoshi; Tobe, Kazuyuki

doi:10.1007/s00125-013-2885-1

Cited by 185 publications

(183 citation statements)

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“…Furthermore, our results could reflect the differences between acute and chronic hypoxia. Examining the role of HIF in ATMs has shown that in vitro exposure to hypoxia increased the expression of IL-6 and IL-1␤ but not TNF-␣, which strongly supports our findings (18). Additionally, Choe et al (47) have shown that knocking down HIF-2␣ enhanced palmitate-induced IL-6 expression, which is also in agreement with our findings.…”

Section: Discussionsupporting

confidence: 92%

“…Recent data suggest that hypoxia in expanding adipose tissue promotes a pro-inflammatory ATM phenotype (18). Although saturated FFA-induced pro-inflammatory signaling pathways in macrophages are well documented (11,14), our understanding of how hypoxia modulates the response of ATMs to saturated FFAs is limited.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia has been shown to increase inflammatory cytokine secretion from macrophages in stromal vascular fractions (19). Furthermore, macrophages derived from hypoxic obese adipose tissue expressed higher levels of the hypoxia-related markers Hif-1␣ and Glut1, the inflammatory marker genes Cd11c and Nos2, and the cytokines Il-6 and Il-1␤ compared with non-hypoxic macrophages (18). These results indicate that adipose tissue hypoxia promotes a pro-inflammatory ATM phenotype.…”

mentioning

confidence: 84%

“…Development of adipose tissue hypoxia is multifactorial and is thought to be driven by adipocyte hypertrophy, compromised vascularization (4,17), and increased adipocyte oxygen consumption through FFA-induced uncoupling (9). Recent studies have suggested hypoxia as a potential cause of the inflammatory changes occurring in obese adipose tissue (9,18,19). Hypoxia has been shown to increase inflammatory cytokine secretion from macrophages in stromal vascular fractions (19).…”

mentioning

confidence: 99%

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Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O 2 ) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1␤. Although palmitate-induced endoplasmic reticulum stress and nuclear factor B pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1␣ and HIF-2␣ alone or in combination failed to reduce IL-6 and only modestly reduced IL-1␤ gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1␤ and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 84%

mentioning

confidence: 99%

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Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

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“…Therefore, although HIF-1a has been reported to influence MP polarization in various tissues (44)(45)(46), HIF-deficient MPs are able to acquire M2 phenotype and functions in sterile inflammation during skeletal muscle regeneration. Phagocytosis of tissue debris is a crucial function of MPs in the resolution of inflammation in skeletal muscle (22,28).…”

Section: Discussionmentioning

confidence: 99%

Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration

Gondin

Théret

Duhamel

et al. 2015

The Journal of Immunology

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International audienceBesides their role in cellular responses to hypoxia, hypoxia-inducible factors (HIFs) are involved in innate immunity and also have anti-inflammatory (M2) functions, such as resolution of inflammation preceding healing. Whereas the first steps of the inflammatory response are associated with proinflammatory (M1) macrophages (MPs), resolution of inflammation is associated with anti-inflammatory MPs exhibiting an M2 phenotype. This M1 to M2 sequence is observed during postinjury muscle regeneration, which provides an excellent paradigm to study the resolution of sterile inflammation. In this study, using in vitro and in vivo approaches in murine models, we demonstrated that deletion of hif1a or hif2a in MPs has no impact on the acquisition of an M2 phenotype. Furthermore, using a multiscale methodological approach, we showed that muscles did not require macrophagic hif1a or hif2a to regenerate. These results indicate that macrophagic HIFs do not play a crucial role during skeletal muscle regeneration induced by sterile tissue damage

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Macrophage metabolism in atherosclerosis

2017

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A key aspect of atherosclerosis is the maladaptive inflammatory response to lipoprotein accumulation in the artery. The failure to decrease lipid accumulation, to clear apoptotic cells, and to resolve inflammation ultimately leads to macrophage accumulation within the vascular wall [Thorp EB (2010) Apoptosis 15, 1124–1136; Moore K et al. (2013) Nat Rev Immunol 13, 709–721; Moore KJ and Tabas I (2011) Cell 145, 341–355; Ley K et al. (2011) Arterioscler Thromb Vasc Biol 31, 1506–1516]. Several subsets of macrophages are found inside atherosclerotic plaques [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17; Leitinger N and Schulman IG (2013) Arterioscler Thromb Vasc Biol 33, 1120–1126; Mantovani A et al. (2009) Arterioscler Thromb Vasc Biol 29, 1419–1423]: Proinflammatory M1‐like macrophages potentially participate in atherosclerosis initiation and progression; M2‐like macrophages are thought to be protective due to their anti‐inflammatory and profibrotic properties, presumably stabilizing the plaque [Chistiakov DA et al. (2015) Int J Cardiol 184, 436–445; Gordon S (2003) Nat Rev Immunol 3, 23–35]; Mox macrophages develop in response to oxidized phospholipids and present a glutathione‐ and potentially redox‐regulating phenotype [Kadl A et al. (2010) Circ Res 107, 737–746]; Mhem macrophages are found in areas of plaque hemorrhage [Boyle JJ et al. (2009) Am J Pathol 174, 1097–1108; Boyle JJ et al. (2012) Circ Res 110, 20–33] where they are involved in heme clearance. Recent evidence suggests that the relative abundance of these macrophage subsets is a better indicator of plaque progression and stability than the total number of lesion macrophages [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17]. Over the last few years, findings in the area of immunometabolism established a link between the metabolic state of the different macrophage phenotypes and their functions [O'Neill LAJ and Pearce EJ (2016) J Exp Med 213, 15–23]. However, the effect of metabolic changes in macrophages on atherosclerotic plaque progression and stability is not well understood and an area of intensive study. In this review, we will summarize and critically discuss recent developments in the field of macrophage metabolism in the context of atherosclerosis to guide future investigation in this area.

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Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice

Abstract: Adipose tissue hypoxia induces an inflammatory phenotype via Hif1a-dependent and Hif1a-independent mechanisms in M1 ATMs but not in M2 ATMs.

Cited by 185 publications

References 43 publications

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration

Macrophage metabolism in atherosclerosis

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