Macrophage polarization in innate immune responses contributing to pathogenesis of chronic kidney disease

Abstract

Chronic kidney disease (CKD) is characterized by inflammation, injury and fibrosis. Dysregulated innate immune responses mediated by macrophages play critical roles in progressive renal injury. The differentiation and polarization of macrophages into pro-inflammatory ‘M1’ and anti-inflammatory ‘M2’ states represent the two extreme maturation programs of macrophages during tissue injury. However, the effects of macrophage polarization on the pathogenesis of CKD are not fully understood. In this review, we discuss the innate immune mechanisms underlying macrophage polarization and the role of macrophage polarization in the initiation, progression, resolution and recurrence of CKD. Macrophage activation and polarization are initiated through recognition of conserved endogenous and exogenous molecular motifs by pattern recognition receptors, chiefly, Toll-like receptors (TLRs), which are located on the cell surface and in endosomes, and NLR inflammasomes, which are positioned in the cytosol. Recent data suggest that genetic variants of the innate immune molecule apolipoprotein L1 (APOL1) that are associated with increased CKD prevalence in people of African descent, mediate an atypical M1 macrophage polarization. Manipulation of macrophage polarization may offer novel strategies to address dysregulated immunometabolism and may provide a complementary approach along with current podocentric treatment for glomerular diseases.

AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization

“…Macrophages that are activated by endogenous and exogenous pathogens are differentiated and polarized into distinct phenotypes through the activation of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and other receptors 37 , 38 . The biological significance of AhR modulate macrophage polarization via these downstream inflammatory signals was documented in several contexts.…”

“…The biological significance of AhR modulate macrophage polarization via these downstream inflammatory signals was documented in several contexts. Toll-like receptor 4 (TLR4) inhibition decreases M1 and enhances M2 macrophage polarization 13 , 37 , 39 . AhR was demonstrated to modulate iNOS and TLR4 expression by competing with hypoxia inducible factor 1-alpha (HIF-1α) for binding to aryl hydrocarbon nuclear translocator (ARNT) 40 .…”

DJ-1 Regulates Microglial Polarization Through P62-Mediated TRAF6/IRF5 Signaling in Cerebral Ischemia-Reperfusion

“…Although there is controversy (Ransohoff, 2016), it is generally believed that after stroke, microglia/macrophage are polarized into the proinflammatory (M1) phenotype and anti-inflammatory (M2) phenotype (Yang et al, 2016). The pro-inflammatory phenotype is characterized by the markers iNOS, CD86, CD16/32, and CD40 (MacMicking et al, 1997;Taylor et al, 2005;Zhou et al, 2017) and the secretion of the proinflammatory cytokines tumor necrosis factor (TNF)-α, IL-1β and IL-6. M2 phenotype cells express high levels of arginase 1 (Arg1), CD163, CD206, and Ym1 (Laffer et al, 2019) and secrete the anti-inflammatory cytokines IL-4 and IL-10 (Rosi, 2016).…”

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

“…The NLRP3 inflammasome is a cytoplasmic multi-protein complex which is comprised of a sensor protein, an adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, a cysteine protease ( Schroder and Tschopp, 2010 ). NLRP3 activation can be primed by toll-like receptors (TLRs) (step 1), which activates NF-κB or a non-NF-κB pathway to produce pro- IL-1β and pro-IL-18; step 2 involves the oligomerization of NLRP3 and recruitment of the adaptor protein ASC and pro-caspase-1 ( Lee et al, 2020 ). Active caspase-1 or caspase-11 then cleaves pro-IL-1β and pro-IL-18 to produce mature cytokines IL-1β and IL-18 ( Lee et al, 2020 ).…”

“…NLRP3 activation can be primed by toll-like receptors (TLRs) (step 1), which activates NF-κB or a non-NF-κB pathway to produce pro- IL-1β and pro-IL-18; step 2 involves the oligomerization of NLRP3 and recruitment of the adaptor protein ASC and pro-caspase-1 ( Lee et al, 2020 ). Active caspase-1 or caspase-11 then cleaves pro-IL-1β and pro-IL-18 to produce mature cytokines IL-1β and IL-18 ( Lee et al, 2020 ). IL-1β and IL-18 are among the most potent pro-inflammatory cytokines and are important in macrophage M1 (pro-inflammatory) polarization ( Lee et al, 2020 ).…”