Natural killer T cell/IL-4 signaling promotes bone marrow-derived fibroblast activation and M2 macrophage-to-myofibroblast transition in renal fibrosis

Liu, Benquan; Jiang, Jun; Liu, Hua; Xiao, Ping; Lai, Xiaomin; Nie, Jiayi; Yu, Wenqiang; Gao, Ying; Wen, Sijian

doi:10.1016/j.intimp.2021.107907

Cited by 26 publications

(14 citation statements)

References 44 publications

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“…Jmjd3 can induce macrophage M2 polarization, which depends on IL-4/STAT6 signaling ( 20 , 28 ). Of note, it has been demonstrated that M2MMT contributes to renal fibrosis progression ( 14 , 37 ). We next examined if Jmjd3 inhibition impairs M2MMT in the FA-treated kidneys.…”

Section: Resultsmentioning

confidence: 99%

Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis

Liu

Gao

et al. 2022

Front. Immunol.

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Renal fibrosis commonly occurs in the process of chronic kidney diseases. Here, we explored the role of Jumonji domain containing 3 (Jmjd3)/interferon regulatory factor 4 (IRF4) axis in activation of myeloid fibroblasts and transition of M2 macrophages into myofibroblasts transition (M2MMT) in kidney fibrosis. In mice, Jmjd3 and IRF4 were highly induced in interstitial cells of kidneys with folic acid or obstructive injury. Jmjd3 deletion in myeloid cells or Jmjd3 inhibitor reduced the levels of IRF4 in injured kidneys. Myeloid Jmjd3 depletion impaired bone marrow-derived fibroblasts activation and M2MMT in folic acid or obstructive nephropathy, resulting in reduction of extracellular matrix (ECM) proteins expression, myofibroblasts formation and renal fibrosis progression. Pharmacological inhibition of Jmjd3 also prevented myeloid fibroblasts activation, M2MMT, and kidney fibrosis development in folic acid nephropathy. Furthermore, IRF4 disruption inhibited myeloid myofibroblasts accumulation, M2MMT, ECM proteins accumulation, and showed milder fibrotic response in obstructed kidneys. Bone marrow transplantation experiment showed that wild-type mice received IRF4-/- bone marrow cells presented less myeloid fibroblasts activation in injured kidneys and exhibited much less kidney fibrosis after unilateral ureteral obstruction. Myeloid Jmjd3 deletion or Jmjd3 inhibitor attenuated expressions of IRF4, α-smooth muscle actin and fibronectin and impeded M2MMT in cultured monocytes exposed to IL-4. Conversely, overexpression IRF4 abrogated the effect of myeloid Jmjd3 deletion on M2MMT. Thus, Jmjd3/IRF4 signaling has a crucial role in myeloid fibroblasts activation, M2 macrophages to myofibroblasts transition, extracellular matrix protein deposition, and kidney fibrosis progression.

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Section: Resultsmentioning

confidence: 99%

Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis

Liu

Gao

et al. 2022

Front. Immunol.

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“…Th2 cytokines jointly play a pivotal role in the onset and progression of liver fibrosis caused by hepatosplenic schistosomiasis [ 21 ], while Th1-specific cytokine INF-γ is involved in the alleviation of hepatic fibrosis [ 22 ]. This could mostly be attributable to the molecular mechanism in which IL-4 is secreted by Th2 cells to tip the macrophage M1/M2 balance to M2 activation [ 23 , 24 ]. Subsequently, M2-type macrophages secrete large amounts of IL-4 to increase Th2 polarization even further.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of PKCλ/ι alleviates the liver pathologic impairment of Schistosoma japonicum infection by thwarting Th2 response

et al. 2022

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Background The activation of immune response driven by the eggs of Schistosoma japonicum and the subsequent secretions is the culprit behind granulomatous inflammation and liver fibrosis. Evidence suggests that PKCλ/ι participates in a variety of physiological and pathological processes, including the regulation of metabolism, growth, proliferation and differentiation of cells. However, the role of PKCλ/ι in liver disease caused by Schistosoma japonicum remains unclear. Methods In the present study, we observe the pathological changes of egg-induced granulomatous inflammation and fibrosis in the liver of mice infected by Schistosoma japonicum by using conditional PKCλ/ι-knockout mice and wild-type control. Immune cytokines and fibrogenic factors were analyzed by performing flow cytometry and real-time fluorescence quantitative PCR. Results The results of H&E and Masson staining show that the degree of granulomatous lesions and fibrosis in the liver of the infected PKCλ/ι-knockout mice was significantly reduced compared with those of the infected wild-type mice. The mean area of single granuloma and hepatic fibrosis in the PKCλ/ι-knockout mice was significantly lower than that of the wild-type mice (85,295.10 ± 5399.30 μm2 vs. 1,433,702.04 ± 16,294.01 μm2, P < 0.001; 93,778.20 ± 8949.05 μm2 vs. 163,103.01 ± 11,103.20 μm2, P < 0.001), respectively. Serological analysis showed that the ALT content was significantly reduced in the infected knockout mice compared with infected wild-type mice. RT-PCR analysis showed that IL-4 content in knockout mice was significantly increased after Schistosoma japonicum infection, yet the increase was less than that in infected wild-type mice (P < 0.05). PKCλ/ι deficiency led to reduced expression of fibrosis-related factors, including TGF-β1, Col-1, Col-3, α-SMA and liver DAMP factor HMGB1. Flow cytometry analysis showed that the increasing percentage of Th2 cells, which mainly secrete IL-4 cytokines in spleen cells, was significantly lower in PKCλ/ι-deficient mice compared with wild-type mice after infection (P < 0.05). Conclusions Our data demonstrate that PKCλ/ι deficiency alleviating granulomatous inflammation and fibrosis in the liver of mice with S. japonicum infection by downregulating Th2 immune response is the potential molecular mechanism behind the role of PKCλ/ι in schistosomiasis. Graphical Abstract

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“…In addition, activation of NKT cells exacerbated the accumulation of MMT in the process of renal fibrosis. Furthermore, administration of IL-4 to CD1d-deficient mice increased bone marrow-derived myofibroblasts, promoted the MMT process, and developed a fibrotic process in the injured kidney (5).…”

Section: Regulation Of Macrophage-tomyofibroblast Transition and Infl...mentioning

confidence: 97%

“…In renal fibrosis, activated myofibroblasts are a critical matrix-secreting cell type that plays a key role in ECM accumulation (5)(6)(7). Myofibroblasts are a heterogeneous population that may be derived from a variety of origins, including epithelia through epithelial-to-mesenchymal transition (EMT) (8,9), endothelia through endothelial-tomesenchymal transition (EndoMT) (10), and local fibroblast or pericyte proliferation (11).…”

Section: Introductionmentioning

confidence: 99%

The role of the macrophage-to-myofibroblast transition in renal fibrosis

2022

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Renal fibrosis causes structural and functional impairment of the kidney, which is a dominant component of chronic kidney disease. Recently, a novel mechanism, macrophage-to-myofibroblast transition (MMT), has been identified as a crucial component in renal fibrosis as a response to chronic inflammation. It is a process by which bone marrow-derived macrophages differentiate into myofibroblasts during renal injury and promote renal fibrosis. Here, we summarized recent evidence and mechanisms of MMT in renal fibrosis. Understanding this phenomenon and its underlying signal pathway would be beneficial to find therapeutic targets for renal fibrosis in chronic kidney disease.

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Natural killer T cell/IL-4 signaling promotes bone marrow-derived fibroblast activation and M2 macrophage-to-myofibroblast transition in renal fibrosis

Cited by 26 publications

References 44 publications

Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis

Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis

Deficiency of PKCλ/ι alleviates the liver pathologic impairment of Schistosoma japonicum infection by thwarting Th2 response

The role of the macrophage-to-myofibroblast transition in renal fibrosis

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