IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages

Yasukawa, Hideo; Ohishi, Masanobu; Mori, Hiroyuki; Murakami, Masaaki; Chinen, Takatoshi; Aki, Daisuke; Hanada, Toshikatsu; Takeda, Kiyoshi; Akira, Shizuo; Hoshijima, Masahiko; Hirano, Toshio; Chien, Kenneth R.; Yoshimura, Akihiko

doi:10.1038/ni938

Cited by 716 publications

(699 citation statements)

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“…To investigate the role that Socs3 in macrophages plays in aortopathy using a mouse model, we deleted the Socs3 gene in macrophages to create mSocs3‐KO mice 10. Aortic stiffening was induced by periaortic application of CaCl 2 , which caused fibrosis and thickening of the abdominal aorta9 that was indistinguishable between WT and mSocs3‐KO mice (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…All animal experiments were done in male mice at the age of 12 to 14 weeks. Macrophage‐specific deletion of Socs3 was achieved by crossing mice with C57BL/6J backgrounds that were homozygous for the floxed allele of Socs3 ( Socs3 fl/fl ) with LysM‐Cre mice in which the Cre recombinase coding sequence was knocked into 1 of the Lyz2 loci 10. Littermate mice without Cre were considered phenotypically wild type (WT) and served as controls.…”

Section: Methodsmentioning

confidence: 99%

“…Toward this end, we investigated the pathological events before AD onset using a mouse aortic stress model9 with macrophage‐specific knockout of Socs3 , a negative feedback factor in Stat3 signaling (mSOCS3‐KO mice) 10, 11. Here, we report a series of pathological events preceding AD onset in which macrophage Socs3 determines whether the aortic tissue adapts to stress or undergoes AD.…”

Section: Introductionmentioning

confidence: 99%

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Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

Ohno‐Urabe

Aoki

Nishihara

et al. 2018

JAHA

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BackgroundAortic dissection (AD) is a life‐threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin‐6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin‐6 in macrophages in pathogenesis of AD.Methods and ResultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild‐type (WT) mice, but progressed to AD in mice with macrophage‐specific deletion of Socs3 gene (mSocs3‐KO). mSocs3‐KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue‐destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction.ConclusionsThese findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

Ohno‐Urabe

Aoki

Nishihara

et al. 2018

JAHA

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“…Furthermore, periarticular adenoviral overexpression of SOCS-3 is effective in attenuating collagen-induced arthritis in mice (31). SOCS proteins, however, might redirect signaling pathways in a concentration-dependent manner (32)(33)(34). In the absence of SOCS-3, prolonged STAT-3 and STAT-1 activation has been observed in vitro and in vivo after stimulation with IL-6.…”

Section: Discussionmentioning

confidence: 99%

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Hooge¹,

Loo²,

Koenders³

et al. 2004

Arthritis & Rheumatism

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Objective. STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT-1, and others have reported preferential activation of STAT-3, in response to endogenous interleukin-6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT-1 and STAT-3 activation in an experimental animal model of arthritis.Methods. Zymosan was injected intraarticularly into naive wild-type (WT), IL-6 ؊/؊ , and STAT-1 ؊/؊ mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene expression of the STATinduced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1 ؊/؊ mice was investigated by reverse transcriptasepolymerase chain reaction.Results. STAT-3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT-1 was observed only during the chronic phase. In IL-6 ؊/؊ mice, STAT activation was limited to STAT-3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL-6 ؊/؊ mice. STAT-1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT-1 ؊/؊ mice, STAT-3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3, gene expression was markedly reduced in STAT-1 ؊/؊ mice.Conclusion. The results in the IL-6 ؊/؊ mice suggest that STAT-3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT-1 ؊/؊ mice suggests an opposing effect of STAT-1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the underlying mechanism by which STAT-1 controls joint inflammation.

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“…Socs3 fl;fl females (Yasukawa et al, 2003) were crossed with MMTV-Cre transgenic males from lines A and D and the WAP-Cre line to yield Socs3 fl/fl; MMTV-Cre and Socs3 fl/fl; WAP-Cre offspring, respectively. Mature females of the CreA line were mated and inspected daily for plugs to determine pregnancy stages.…”

Section: Experimental Procedures Animalsmentioning

confidence: 99%