Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Masuda, Tomohiro; Maeda, Kayaho; Sato, Waichi; Kosugi, Tomoki; Sato, Yuka; Kojima, Hiroshi; Kato, Noritoshi; Ishimoto, Takuji; Tsuboi, Naotake; Uchimura, Kenji; Yuzawa, Yukio; Maruyama, Shoichi; Kadomatsu, Kenji

doi:10.1016/j.ajpath.2016.12.006

Cited by 25 publications

(24 citation statements)

References 50 publications

(59 reference statements)

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“…CD4+ T cells play an important role in mesangial proliferative glomerulonephritis (MsPGN) [44, 45]. CD4+ T cells that recognize specific antigens deposited in the glomerular mesangium cause glomerulonephritis-like kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses

Cui

Mei

et al. 2019

Journal of Immunology Research

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Background. Mesangial cells play a prominent role in the development of inflammatory diseases and autoimmune disorders of the kidney. Mesangial cells perform the essential functions of helping to ensure that the glomerular structure is stable and regulating capillary flow, and activated mesangial cells acquire proinflammatory activities. We investigated whether activated mesangial cells display immune properties and control the development of T cell immunity. Methods. Flow cytometry analysis was used to study the expression of antigen-presenting cell surface markers and costimulatory molecules in mesangial cells. CD4+ T cell activation induced by mesangial cells was detected in terms of T cell proliferation and cytokine production. Results. IFN-γ-treated mesangial cells express membrane proteins involved in antigen presentation and T cell activation, including MHC-II, ICAM-1, CD40, and CD80. This finding suggests that activated mesangial cells can take up and present antigenic peptides to initiate CD4+ T cell responses and thus act as nonprofessional antigen-presenting cells. Polarization of naïve CD4+ T cells (Th0 cells) towards the Th1 phenotype was induced by coculture with activated mesangial cells, and the resulting Th1 cells showed increased mRNA and protein expression of inflammation-associated genes. Conclusion. Mesangial cells can present antigen and modulate CD4+ T lymphocyte proliferation and differentiation. Interactions between mesangial cells and T cells are essential for sustaining the inflammatory response in a variety of glomerulonephritides. Therefore, mesangial cells might participate in immune function in the kidney.

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Section: Discussionmentioning

confidence: 99%

Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses

Cui

Mei

et al. 2019

Journal of Immunology Research

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“…In inflammation process, MK induces cytokines and modulates migration of neutrophils and macrophages. MK activates T splenocytes, Th1 cell differentiation and has functioned as a negative immune modulator of Tregs in peripheral lymph nodes [ 16 ]. Inhibition of MK leads to an increase in Treg expansion and then suppresses the autoreactive Th1 cell population thus causing the reduced severity of the autoimmune disease [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Serum Midkine Levels in Systemic Lupus Erythematosus

Marpaung¹,

Ginting²,

Sjah³

2018

Open Access Maced J Med Sci

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BACKGROUND:Midkine (MK) induces inflammation and could inhibit inducible regulatory T cell differentiation. These reports suggest that MK may play a role in the pathogenesis of autoimmune disease including SLE, but data about MK in SLE patients was still limited, and the role of Midkine in SLE is largely unknown.AIM:The purpose of this study was to compare serum level MK in SLE patients and control, also analysed the relationship between the serum MK level and disease activity in SLE.METHODS:This cross-sectional study was conducted in Adam Malik Hospital from January-June 2017. Diagnosis of SLE was established according to the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, and disease activity was assessed using the Mexican Systemic lupus erythematosus disease activity index (MEX-SLEDAI). Subjects with evidence of malignancy and systemic disease (pulmonary, kidney, liver, metabolic disorder, etc.) were excluded. Data analysis was performed using SPSS 22nd version. P < 0.05 was considered statistically significant.RESULTS:There were 90 subjects and divided into 2 groups: SLE patients group (n=40) and healthy control groups (n = 50). Midkine levels were increased in the serum of SLE patients compared by health control. There was a significant difference in the median serum Midkine levels between SLE patients and healthy control (P < 0.001). Elevated Midkine serum levels were a significant difference between active disease and remission (P = 0.018).CONCLUSION:Elevated Midkine serum level could be a marker of SLE disease activity and have a role in the pathogenesis of SLE.

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“…3b,c). MDK has been reported to signal through multiple different intracellular pathways involving Akt, Atf 21 , Stat4, NFAT1, NFAT2 22 , and Src 23 . While no differences in Akt, Atf, Stat4, NFAT2 activation were observed ( Supplementary Fig.…”

Section: Mdk Induces T Cell Ccl4 Via Lrp1/calcineurin/nfat1 Signalingmentioning

confidence: 99%

Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

et al. 2020

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Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1mutant human and mouse brain neurons elaborate midkine to activate naïve CD8 + T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

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Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Cited by 25 publications

References 50 publications

Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses

Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses

Serum Midkine Levels in Systemic Lupus Erythematosus

Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

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