IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses

Krausgruber, Thomas; Blazek, Katrina; Smallie, Tim; Alzabin, Saba; Lockstone, Helen; Sahgal, Natasha; Hussell, Tracy; Feldmann, Marc; Udalova, Irina A.

doi:10.1038/ni.1990

Cited by 1,112 publications

(1,057 citation statements)

References 49 publications

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“…However, the reason for the delayed signaling activation induced by IL-32g is still unclear, because no IL-32-specific receptor has yet been identified, although IL-32 was reported to interact with integrins such as aVb3 and aVb6 through its Arg-Gly-Asp (RGD) motif (42). Further functional and transcriptional analyses, including the expression of transcription factors, such as IRF4 (43) and IRF5 (44), are needed to understand how M-CSF and IL-32g influence each other during the regulation of the phenotypes and functions of macrophages. Despite these unresolved issues, the findings regarding the unique functional interplay between M-CSF and IL-32g presented in this article increase our understanding of the mechanisms that regulate the survival and M1/ M2 ratio of macrophages, as well as HIV-1 replication in macrophages.…”

Section: Discussionmentioning

confidence: 99%

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Osman

Bhuyan

Hashimoto

et al. 2014

The Journal of Immunology

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M-CSF promotes the differentiation and survival of macrophages, and preferentially induces anti-inflammatory M2, rather than proinflammatory M1 macrophages. Recently, another cytokine, IL-32, was also shown to promote macrophage differentiation. In this article, we provide the first evidence, to our knowledge, that M-CSF has both additive and inhibitory effects on the macrophage-related activities of IL-32. When added to M-CSF–derived macrophages, M-CSF and IL-32 promoted macrophage survival, which was further enhanced by their combination. However, they had different effects on HIV-1 replication; that is, it was stimulated by M-CSF and inhibited by IL-32. Interestingly, the anti–HIV-1 activity of IL-32 was counteracted by M-CSF. Such inhibitory effect of M-CSF was not observed with IL-32–induced M1-like features including high cytokine/chemokine production and strong expression of the costimulatory molecule CD80. However, IL-32–treated macrophages unexpectedly showed also M2-like features including increased phagocytic activity, and high expression of CD14 and the scavenger receptor CD163, and the expression of CD14 and CD163 was further upregulated by cotreatment with M-CSF. The findings of this study regarding the unique functional interplay between M-CSF and IL-32 increase our understanding of the mechanisms that regulate the survival and M1/M2 ratio of macrophages, as well as HIV-1 replication in macrophages.

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Section: Discussionmentioning

confidence: 99%

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Osman

Bhuyan

Hashimoto

et al. 2014

The Journal of Immunology

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“…In acid aspiration lung injury, TLR4/TRIF/TRAF6 signaling in lung macrophages was shown to determine the susceptibility to ARDS in vivo (12,33). Both TRAF6 and IRF5 lead to NF-kB activation, but IRF5 is also an important regulator of iNOS and IL-12b expression and, thus, M1 polarization (23,52,(57)(58)(59)(60). We found that WT macrophages upregulate TRAF6 and IRF5 gene expression in line with their M1 phenotype, whereas Akt2-deficient macrophages, having an M2 phenotype, exhibit reduced levels of these factors both at baseline and upon acid injury.…”

Section: Discussionmentioning

confidence: 99%

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

147

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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“…Tissue macrophages display enormous functional and phenotypical plasticity in response to changing microenvironmental stimuli [42,43]. Under steady-state conditions, macrophages support either homeostatic processes or trophic processes for tissue development/remodeling in developing or healing tissues [4,5].…”

Section: Development and Functions Of Macrophagesmentioning

confidence: 99%

Monocytes and Macrophages in Cancer: Development and Functions

Richards

Hettinger

Feuerer

2012

Cancer Microenvironment

171

122

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Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumorassociated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.

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IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses

Cited by 1,112 publications

References 49 publications

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Monocytes and Macrophages in Cancer: Development and Functions

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