Identification of the HSPB4/TLR2/NF‐κB axis in macrophage as a therapeutic target for sterile inflammation of the cornea

Oh, Joo Youn; Choi, Hosoon; Lee, Ryang Hwa; Roddy, Gavin W.; Ylöstalo, Joni; Wawrousek, Eric F.; Prockop, Darwin J.

doi:10.1002/emmm.201200221

Cited by 45 publications

(49 citation statements)

References 43 publications

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“…In CD44 knockout mice, bleomycin induced an unrelenting inflammatory response in a TLR2-and TLR4-dependent manner (14,45). TSG-6 was also effective in wild-type mice but ineffective in CD44 knockout mice employed in a mouse model for sterile injury to the cornea (28). In the present study, we employed the CD44 knockout mouse model, similar to that used in the study by Choi et al In these mice, CD44 expression is constitutively knocked out in all cell lineages and not restricted to only macrophages.…”

Section: Discussionmentioning

confidence: 99%

Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs

Foskett¹,

Bazhanov²,

Ti³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs

Foskett¹,

Bazhanov²,

Ti³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Gene expression of Ccl12 was significantly reduced at both 14 and 28 days post-exposure whereas only Il1β gene expression was significantly depressed at 28 days post-exposure. Ntrk1 , Kcnq3 and Oprd1 play important roles in neuropathic pain (Benbouzid et al, 2008; Dondio et al, 2001; Dost et al, 2004; Fritch et al, 2010; Ma et al, 2010; Shinoda et al, 2007; Ugolini et al, 2007) while Ccl12 , Tlr2 , and Il1β are involved in inflammation (Gundra et al, 2011; Mojsilovic-Petrovic et al, 2007; Niven et al, 2015; Oh et al, 2012; Yang et al, 2009). Ntrk1 also may be a part of a negative feedback loop linking neuropathic pain and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

Manohar

Dahar

Adler

et al. 2016

Molecular and Cellular Neuroscience

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Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2 h to a 126 dB SPL narrow band noise centered at 12 kHz. Hearing loss measured by auditory brainstem responses exceeded 55 dB from 6 to 32 kHz. The mRNA from the exposed CN was harvested at 14 or 28 days post-exposure and qRT-PCR analysis was performed on 168 genes involved in neural inflammation, neuropathic pain and glutamatergic or GABAergic neurotransmission. Expression levels of mRNA of Slc17a6 and Gabrg3, involved in excitation and inhibition respectively, were significantly increased at 28 days post-exposure, suggesting a possible role in the CN spontaneous hyperactivity associated with tinnitus and hyperacusis. In the pain and inflammatory array, noise exposure up-regulated mRNA expression levels of four pain/inflammatory genes, Tlr2, Oprd1, Kcnq3 and Ntrk1 and decreased mRNA expression levels of two more genes, Ccl12 and Il1β. Pain/inflammatory gene expression changes via Ntrk1 signaling may induce sterile inflammation, neuropathic pain, microglial activation and migration of nerve fibers from the trigeminal nerve and cuneate and vestibular nuclei into the CN. These changes could contribute to somatic tinnitus, hyperacusis and otalgia.

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“…In another study, TSG6 prevented zymosan-induced peritonitis secondary to reduced TLR2-mediated nuclear translocation of NF-κB (12). TSG6 also has been shown to reduce inflammation by inhibiting NF-κB signaling in a model of sterile injury of the cornea (11,31). Although the anti-inflammatory effects of TSG6 have been well described (1, 2, 7-14, 29, 32), how it modulates inflammation has not been addressed until now.…”

Section: Tsg6 Treatment Prevents Lps-induced Lung Vascular Injury Nementioning

confidence: 99%

TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury

Mittal

Tiruppathì

Nepal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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167

148

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TNFα-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Here we observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6 −/− mice compared with WT (TSG6 +/+ ) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-κB activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNFα, IL-1β, and CXCL1) while increasing the expression of antiinflammatory proteins (CD206, Chi3l3, IL-4, and IL-10) in macrophages. This shift was associated with suppressed activation of proinflammatory transcription factors STAT1 and STAT3. In addition, we observed that LPS itself up-regulated the expression of TSG6 in TSG6 +/+ mice, suggesting an autocrine role for TSG6 in transitioning macrophages. Thus, TSG6 functions by converting macrophages from a proinflammatory to an anti-inflammatory phenotype secondary to suppression of TLR4/NF-κB signaling and STAT1 and STAT3 activation. However, there appears to be little constitutive expression of TSG6 (3). TSG6 is synthesized in response to proinflammatory mediators, including lipopolysaccharide (LPS), TNFα, and IL-1β (3-5). TSG6 is composed of an HA-binding LINK domain and a CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor, and bone morphogenetic protein) domain (3, 4) To date, only the HA-binding protein CD44 has been shown to function as a TSG6 receptor (6).TSG6 has a potent but poorly understood function in suppressing inflammation through inhibition of neutrophil migration and production of proinflammatory cytokines (7,8). This effect of TSG6 has been demonstrated in several models. TSG6 was shown to prevent inflammation and tissue injury in rodent models of arthritis (9), myocardial infarction (10), corneal injury (11), and peritonitis (12). Both IL-1β and TNFα induced the synthesis of TSG6 in MSCs, monocytes/macrophages, and fibroblasts (2, 4, 5). Administration of human MSCs in mice prevented endotoxin (LPS)-induced acute lung injury (ALI), and, importantly, this effect was abrogated using cells pretreated with TSG6-siRNA to suppress TSG6 expression (13). TSG6 also delayed the onset of autoimmune diabetes by suppressing the activation of T cells and antigen-presenting cells (14), further supporting its role in dampening the adaptive immune response.In the present study, we addressed the role of TSG6 in ALI, an acute inflammatory disease that injures the lung's vascular barrier, resulting in severe protein-rich pulmonary edema and hypoxemia, associated with ∼50% mortality (15). There is a profound release of proinflammatory cytotoxic mediators from activated alveolar macrophages and other inflammatory cells sequestered in lungs (15). Macrophages in ALI are a...

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Identification of the HSPB4/TLR2/NF‐κB axis in macrophage as a therapeutic target for sterile inflammation of the cornea

Cited by 45 publications

References 43 publications

Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs

Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling

TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury

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