Roles and crosstalks of macrophages in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.

Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets

“…Meanwhile, DN context prompts the activated resident macrophages and renal parenchymal cells, such as glomerular podocytes, to secrete chemokines such as Myd88, C-C motif chemokine ligand 2 (CCL2), CCL5, and CSF-1, recruiting circulating monocytes, orchestrating the infiltration of macrophages within the kidney and ultimately facilitating the pathogenesis of kidney diseases. 23 As a highly plastic, diverse and heterogeneous class of cells, macrophages are traditionally divided into two phenotypes according to the expression of cell markers and biological activity: M1type macrophages (activated through classical pathways) and M2-type macrophages (also known as alternative activated macrophages). 26 Macrophages polarize into M1 phenotype upon the inflammatory cytokines or microbial molecules like interferon-γ and lipopolysaccharide (LPS), whereas interleukin (IL)-4 and IL-13 can promote their polarization to M2 phenotype.…”

“…Therefore, at the initial stage of DN, kidney‐resident macrophages are rapidly activated by stimuli in the kidney acting as gatekeepers, as high glucose induces adhesion molecules including intercellular adhesion molecule‐1 (ICAM‐1) and vascular cellular adhesion molecule 1 (VCAM‐1) in vascular endothelial cells, podocytes, and mesangial cells, which are key molecules promoting renal macrophage recruitment in DN. Meanwhile, DN context prompts the activated resident macrophages and renal parenchymal cells, such as glomerular podocytes, to secrete chemokines such as Myd88, C–C motif chemokine ligand 2 (CCL2), CCL5, and CSF‐1, recruiting circulating monocytes, orchestrating the infiltration of macrophages within the kidney and ultimately facilitating the pathogenesis of kidney diseases 23 . As a highly plastic, diverse and heterogeneous class of cells, macrophages are traditionally divided into two phenotypes according to the expression of cell markers and biological activity: M1‐type macrophages (activated through classical pathways) and M2‐type macrophages (also known as alternative activated macrophages) 26 .…”

“…[19][20][21] Kidney-resident macrophages originate from early yolk sac progenitors and later from fetal liver and hematopoietic stem cells. 22,23 They facilitate renal organogenesis by branching morphogenesis and clearing cellular debris, and are primarily situated at the abluminal side of peritubular capillaries, where they incessantly surveil endothelial transport and recognize, as well as scavenge, circulating immune complexes and particles entering the renal interstitium. [22][23][24][25] Therefore, at the initial stage of DN, kidney-resident macrophages are rapidly activated by stimuli in the kidney acting as gatekeepers, as high glucose induces adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule 1 (VCAM-1) in vascular endothelial cells, podocytes, and mesangial cells, which are key molecules promoting renal macrophage recruitment in DN.…”

“…22,23 They facilitate renal organogenesis by branching morphogenesis and clearing cellular debris, and are primarily situated at the abluminal side of peritubular capillaries, where they incessantly surveil endothelial transport and recognize, as well as scavenge, circulating immune complexes and particles entering the renal interstitium. [22][23][24][25] Therefore, at the initial stage of DN, kidney-resident macrophages are rapidly activated by stimuli in the kidney acting as gatekeepers, as high glucose induces adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule 1 (VCAM-1) in vascular endothelial cells, podocytes, and mesangial cells, which are key molecules promoting renal macrophage recruitment in DN. Meanwhile, DN context prompts the activated resident macrophages and renal parenchymal cells, such as glomerular podocytes, to secrete chemokines such as Myd88, C-C motif chemokine ligand 2 (CCL2), CCL5, and CSF-1, recruiting circulating monocytes, orchestrating the infiltration of macrophages within the kidney and ultimately facilitating the pathogenesis of kidney diseases.…”

“…Kidney‐resident macrophages originate from early yolk sac progenitors and later from fetal liver and hematopoietic stem cells 22,23 . They facilitate renal organogenesis by branching morphogenesis and clearing cellular debris, and are primarily situated at the abluminal side of peritubular capillaries, where they incessantly surveil endothelial transport and recognize, as well as scavenge, circulating immune complexes and particles entering the renal interstitium 22–25 …”