TNF Counterbalances the Emergence of M2 Tumor Macrophages

Kratochvill, Franz; Neale, Geoffrey; Haverkamp, Jessica M.; Velde, Lee Ann Van de; Smith, Amber M.; Kawauchi, Daisuke; McEvoy, Justina; Roussel, Martine F.; Dyer, Michael A.; Qualls, Joseph E.; Murray, Peter J.

doi:10.1016/j.celrep.2015.08.033

Cited by 239 publications

(207 citation statements)

References 67 publications

(92 reference statements)

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“…These cells suppress inflammatory arthritis and hence its osteolytic consequences (86). TNF-α, which promotes osteoclast formation, blunts polarization to the M2 phenotype directly and by arresting production of IL-13 by eosinophils that are present in arthritic joints (86,87). While these observations suggest that osteoclasts are not derived from alternatively activated M2 macrophages, inflammatory arthritis in mice recruits osteoclast precursors with features of both M1 and M2 cells (88).…”

Section: Immunoregulatory Mechanisms Inhibiting Focal Arthritic Osteomentioning

confidence: 75%

Inflammatory osteolysis: a conspiracy against bone

Mbalaviele¹,

Novack

Schett

et al. 2017

Journal of Clinical Investigation

200

178

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Section: Immunoregulatory Mechanisms Inhibiting Focal Arthritic Osteomentioning

confidence: 75%

Inflammatory osteolysis: a conspiracy against bone

Mbalaviele¹,

Novack

Schett

et al. 2017

Journal of Clinical Investigation

200

178

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“…Indeed, a recent work reveals that TNFα, which is increased in the injured spinal cord for the first 24 hours, prevents the induction of M2 markers in microglia and macrophages after SCI (Kroner et al 2014), as well as in tumor macrophages (Kratochvill et al 2015). It is likely that other pro-inflammatory cytokines and/or mediators synthesized during the first few hours post-injury could also exert a similar effect.…”

Section: Discussionmentioning

confidence: 99%

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Francos-Quijorna

Amo-Aparicio

Martínez-Muriana

2016

Glia

162

135

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"This is the peer reviewed version of the following article: Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, López-Vales R. IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair andfunctional recovery after spinal cord injury. Glia. 2016 Dec;64(12):2079-2092 ABSTRACTMacrophages and microglia play a key role in the maintenance of nervous system homeostasis.However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments.

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“…Also, LysM-Cre conditional knockout mice would not only lack NFAT5 in different macrophage subsets but also in other myeloid cells such as neutrophils and dendritic cells, whose pro-and antiinflammatory activity at different stages of tumor development may contribute with variable outcomes to tumor progression. In this regard, it has been shown that macrophages at different intratumoral maturation stages can differ considerably in expression patterns of pro-and anti-inflammatory genes (12).…”

Section: Nfat5 Influences Macrophage-mediated Antitumor Responses Inmentioning

confidence: 99%

“…The capacity of macrophages to function in pro-or anti-inflammatory modes plays a key role in both the triggering and resolution of immune responses, but can also constitute a potential vulnerability for the immune system as imbalances in macrophage function can lead to pathological immune reactivity or tolerance. In this regard, the tumor microenvironment provides an interesting scenario, where despite proinflammatory and potentially antitumor macrophages being found (7), anti-inflammatory macrophages are the dominant type and control tumor progression by performing key protumoral trophic and immunotolerant functions (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

Tellechea

Buxadé

Tejedor

et al. 2018

The Journal of Immunology

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Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions.

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TNF Counterbalances the Emergence of M2 Tumor Macrophages

Cited by 239 publications

References 67 publications

Inflammatory osteolysis: a conspiracy against bone

Inflammatory osteolysis: a conspiracy against bone

IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

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