Role of Macrophages and Related Cytokines in Kidney Disease

Abstract

Inflammation is a key characteristic of kidney disease, but this immune response is two-faced. In the acute phase of kidney injury, there is an activation of the immune cells to fight against the insult, contributing to kidney repair and regeneration. However, in chronic kidney diseases (CKD), immune cells that infiltrate the kidney play a deleterious role, actively participating in disease progression, and contributing to nephron loss and fibrosis. Importantly, CKD is a chronic inflammatory disease. In early CKD stages, patients present sub-clinical inflammation, activation of immune circulating cells and therefore, anti-inflammatory strategies have been proposed as a common therapeutic target for renal diseases. Recent studies have highlighted the plasticity of immune cells and the complexity of their functions. Among immune cells, monocytes/macrophages play an important role in all steps of kidney injury. However, the phenotype characterization between human and mice immune cells showed different markers; therefore the extrapolation of experimental studies in mice could not reflect human renal diseases. Here we will review the current information about the characteristics of different macrophage phenotypes, mainly focused on macrophage-related cytokines, with special attention to the chemokine CCL18, and its murine functional homolog CCL8, and the macrophage marker CD163, and their role in kidney pathology.

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…Indeed, this pathological response commonly appears in many chronic kidney diseases including diabetic nephropathy, hypertensive nephropathy, primary chronic glomerulonephritis, chronic interstitial glomerulonephritis, and chronic tubular disease, and may be the cause of renal failure and death [ 138 , 139 ]. Therefore, renal fibrosis arises as an attempt to repair the tissue in a context of chronic kidney inflammation, which may initiate as a response to different stimuli such as toxins, xenobiotics, infections, or genetic disorders, and become pathologically persistent [ 140 ], predisposing the patient to develop any form of the chronic kidney diseases previously mentioned [ 141 ].…”

“…On the other hand, M2 macrophages (CD11b+/Ly6C int ), which highly express Arg1, CD206, and chitinase-like proteins such as Ym1, Fizz1, and CD36, are in charge of repairing the affected tissue by secreting TGF-β, CCL17, CCL18, and CCL22, among others. The transition from one phenotype to the other is driven by the presence of high levels of IL-4, IL-10, and IL-13 [ 141 ]. The prolonged activity of M2 macrophages (CD11b+/Ly6C low ) is responsible for the exacerbated fibrotic tissue deposition and accumulation by producing PDGF, IGF-1, and CCL17 [ 143 ].…”

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

“…This chemokine is one of the most highly expressed in human chronic inflammatory diseases, including allergies, fibrotic disorders and certain cancers [43], and is secreted in high amounts by M2 macrophages [44]. The functional analogue of human CCL18 is mouse Ccl8 and both share CCR8 as functional receptor [30,31]. Interestingly, CD163+/CCL18 expressing macrophages colocalized with Gremlin-1 protein expression in ANCA-associated cGN patients [13].…”

“…The chemokine (C-C motif) ligand 18 (CCL18) has been recently proposed as a potential biomarker of human cGN [29], therefore we evaluated the expression of Ccl8, the murine functional human CCL18 homologue [30,31]. In NTS mice, ccl8 gene expression was upregulated in injured kidneys and diminished by JQ1 treatment (Figure 6A).…”

“…In the kidney, Gremlin-1 activates several downstream pathways, including nuclear factor-κB (NF-κB) and NOTCH, linked to inflammation and kidney injury [22][23][24][25]. The NOTCH signaling pathway is activated in CKD, including glomerular diseases such as diabetic kidney disease (DKD), IgA nephropathy, and focal segmental glomerulosclerosis (FSGS) [26][27][28][29][30]. Activation of NOTCH is mediated by successive proteolytic cleavages of the NOTCH receptor that release its intracellular domain (NICD) from the cellular membrane.…”