HtrA2 suppresses autoimmune arthritis and regulates activation of STAT3

Lee, Jun Young; Moon, Young Myoung; Seo, Hyeon-Beom; Kim, Seyoung; Kim, Min Jung; Yi, Junyeong; Nam, Min-Kyung; Min, Jun‐Ki; Park, Sung-Hwan; Rhim, Hyangshuk; Cho, Mi‐La

doi:10.1038/srep39393

Cited by 18 publications

(8 citation statements)

References 46 publications

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“…Th17 cells are pathogenic factors in several autoimmune diseases, and inhibition of Th17 cell differentiation diminishes inflammatory disorders [ 29 – 31 ]. Downregulation of Th17 cell populations leads to attenuation of CIA [ 32 ]. On the other hand, Treg cells show an immunosuppressive function; thus, a reciprocal balance between Th17 and Treg cells is important to diminishing CIA [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

et al. 2019

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BackgroundRheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis.MethodsWe investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA).ResultsNST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice.ConclusionsThese results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.

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Section: Discussionmentioning

confidence: 99%

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

et al. 2019

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“…Another study has shown that HTRA2 suppresses cell proliferation through binding to WARTS (WTS)/large tumor-suppressor 1 mitotic kinase (Kuninaka et al, 2007). HTRA2 cleaves STAT3 protein to modulate expression of cytokines that regulate T cell proliferation (Lee et al, 2016). These studies indicate that HTRA2 cleaves multiple substrates, including proteins that directly regulate the cell cycle, or indirectly, through modulating activity of transcription factors involved in cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Role of ALDH1A1 and HTRA2 expression to CCL2/CCR2 mediated breast cancer cell growth and invasion

Myers

Fang

et al. 2019

Biology Open

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Chemokines mediate immune cell trafficking during tissue development, wound healing and infection. The chemokine CCL2 is best known to regulate macrophage recruitment during wound healing, infection and inflammatory diseases. While the importance of CCL2/CCR2 signaling in macrophages during cancer progression is well documented, we recently showed that CCL2-mediated breast cancer progression depends on CCR2 expression in carcinoma cells. Using 3D Matrigel: Collagen cultures of SUM225 and DCIS.com breast cancer cells, this study characterized the mechanisms of CCL2/CCR2 signaling in cell growth and invasion. SUM225 cells, which expressed lower levels of CCR2 than DCIS.com cells, formed symmetrical spheroids in Matrigel: Collagen, and were not responsive to CCL2 treatment. DCIS.com cells formed asymmetric cell clusters in Matrigel: Collagen. CCL2 treatment increased growth, decreased expression of E-cadherin and increased TWIST1 expression. CCR2 overexpression in SUM225 cells increased responsiveness to CCL2 treatment, enhancing growth and invasion. These phenotypes corresponded to increased expression of Aldehyde Dehydrogenase 1A1 (ALDH1A1) and decreased expression of the mitochondrial serine protease HTRA2. CCR2 deficiency in DCIS.com cells inhibited CCL2-mediated growth and invasion, corresponding to decreased ALDH1A1 expression and increased HTRA2 expression. ALDH1A1 and HTRA2 expression were modulated in CCR2-deficient and CCR2-overexpressing cell lines. We found that ALDH1A1 and HTRA2 regulates CCR2-mediated breast cancer cell growth and cellular invasion in a CCL2/CCR2 context-dependent manner. These data provide novel insight on the mechanisms of chemokine signaling in breast cancer cell growth and invasion, with important implications on targeted therapeutics for anti-cancer treatment.

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“…Activation of STAT3 leads to increased proinflammatory cytokine production and immune responses (11, 12). Recent reports have shown that inhibition of STAT3 improves experimental autoimmune arthritis by limiting the immune–inflammatory response (13–15). STAT3 activation has also been shown to be significantly higher in chondrocytes from OA patients than in those from normal controls (16).…”

Section: Introductionmentioning

confidence: 99%

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

Lee

et al. 2018

Front. Immunol.

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Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation. Signal transducer and activator of transcription 3 (STAT3) modulates secretion of many proinflammatory cytokines. Experimental OA was induced by intra-articular (IA) injection of monosodium iodoacetate (MIA) to the right knee of rats. MSCs from OA patients (OA-MSCs) were treated with STA21, a small molecule that blocks STAT3 signaling, by IA or intravenous (IV) injection after MIA injection. Pain severity was quantified by assessment of secondary tactile allodynia using the von Frey assessment test. Cartilage degradation was measured by microcomputed tomography image analysis, histological analysis, and the Mankin score. Protein and gene expression was evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and real-time polymerase chain reaction. MSCs increased production of proinflammatory cytokines under inflammatory conditions. STA21 significantly decreased expression of these proinflammatory molecules via inhibition of STAT3 activity but increased gene expression of molecules related to migration potential and immunomodulation in OA-MSCs. STAT3-inhibited OA-MSCs administrated by IV or IA injection decreased pain severity and cartilage damage in rats with MIA-induced OA rats by decreasing proinflammatory cytokines in the joints. Combined IA and IV-injected STAT3-inhibited OA-MSCs had an additive effect of pain relief in MIA-induced OA rats. STAT3 inhibition may optimize the therapeutic activities of MSCs for treating OA by attenuating pain and progression of MIA by inhibiting inflammation and cartilage damage.

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HtrA2 suppresses autoimmune arthritis and regulates activation of STAT3

Cited by 18 publications

References 46 publications

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis

Role of ALDH1A1 and HTRA2 expression to CCL2/CCR2 mediated breast cancer cell growth and invasion

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

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