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

Abstract

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.

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6‐dependent STAT3 pathway

“…Bae et al demonstrated that glycolysis negatively regulates proinflammatory responses in inflammatory macrophages by mediating IRF4 17 . Liang et al indicated that Jmjd3/IRF4 axis is involved in myofibroblast transition in renal fibrosis via aggravating myeloid fibroblast activation as well as M2 macrophage 34 . Additionally, Shohan et al indicated that IRF4 expression was elevated in the inflamed mucosa of UC patients, mirroring that IRF4 has a crucial role in UC development 35 .…”

“…(A) and (B) flow cytometry analysis was used to detect the percentage of CD11b + CD86 + cells and CD11b + CD86 + cells affected by Bcl6 and recovered by IRF4 in dextran sulfate sodium (DSS) induced UC mice; (C) enzyme-linked immunosorbent assay was used to detect the secretion of TNF-α, IL-1β, IL-6, and IL-10 affected by Bcl6 and recovered by IRF4 in DSS induced ulcerative colitis (UC) mice. *, p < .05; ****, p < .0001.Jmjd3/IRF4 axis is involved in myofibroblast transition in renal fibrosis via aggravating myeloid fibroblast activation as well as M2 macrophage 34. Additionally, Shohan et al indicated that IRF4 expression was elevated in the inflamed mucosa of UC patients, mirroring that IRF4 has a crucial role in UC development 35.…”

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis

“…This population of cells may arise from a further differentiation of M2, as evidenced by the expression of M2 markers including CD206 ( 22 ). Over the past few years, several studies conducted by different research groups have reported the presence of MMT and its critical role in kidney fibrosis ( 14 , 22 , 23 , 79 , 80 ). However, recent single-cell sequencing data does not provide substantial evidence supporting a significant contribution of myofibroblasts originating from macrophages ( 10 ).…”

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

“…JAK3/STAT6 signaling, Jumonji domain containing 3 (Jmjd3)/interferon regulatory factor 4 (IRF4) axis, and natural killer T cell/IL-4 signaling can activate myeloid fibroblasts, promoting the transition of M2 macrophages into myofibroblasts in kidney fibrosis in obstructed mouse kidneys [216][217][218]. Myeloid Jmjd3 deletion or Jmjd3 inhibitor reduced the expression of IRF4, α-smooth muscle actin, and fibronectin, inhibiting MMT in cultured monocytes exposed to IL-4.…”