Abstract
Macrophage M1 polarization mediates inflammatory responses and tissue damage. Recently, aldose reductase (AR) has been shown to play a critical role in M1 polarization in macrophages. However, the underlying mechanisms are unknown. Here, we demonstrated, for the first time, that AR deficiency repressed the induction of inducible nitric oxide synthase in lipopolysaccharide (LPS)-stimulated macrophages via activation of autophagy. This suppression was related to a defect in the inhibitor of nuclear factor κB (NF-κB) kinase (IKK) complex in the classical NF-κB pathway. However, the mRNA levels of IKKβ and IKKγ were not reduced in LPS-treated AR knockout (KO) macrophages, indicating that their proteins were downregulated at the post-transcriptional level. We discovered that LPS stimuli induced the recruitment of more beclin1 and increased autophagosome formation in AR-deficient macrophages. Blocking autophagy through 3-methyladenine and ammonium chloride treatment restored IKKβ and IKKγ protein levels and increased nitric oxide synthase production in LPS-stimulated AR-deficient macrophages. More assembled IKKβ and IKKγ underwent ubiquitination and recruited the autophagic adaptor p62 in LPS-induced AR KO macrophages, promoting their delivery to autophagosomes and lysosomes. Collectively, these findings suggest that AR deficiency is involved in the regulation of NF-κB signaling, and extends the role of selective autophagy in fine-tuned M1 macrophage polarization.
Highlights
Macrophages demonstrate significant plasticity and can modify their phenotype and function in response to their microenvironment [1]
Since inflammatory signals and immune responses are tightly correlated with macrophage polarization, we investigated changes in the expression of Aldose reductase (AR) upon LPS stimulation in BMMs from wild type (WT) C57BL/6 mice
Our results showed that AR deficiency led to the suppression of the M1 phenotype in macrophages, limiting its pro-inflammatory activity through the degradation of a key component of the IKK complex
Summary
Macrophages demonstrate significant plasticity and can modify their phenotype and function in response to their microenvironment [1]. In response to lipopolysaccharide (LPS) treatment, either alone or in combination with pro-inflammatory cytokines such as interferon-γ, macrophages undergo. Aldose reductase (AR), a rate-limiting enzyme in the polyol pathway that catalyzes the reduction of glucose to sorbitol in the presence of reduced nicotinamide adenine dinucleotide phosphate, has emerged as a molecular target in multiple inflammatory diseases [4]. Ravindranath et al demonstrated that transgenic mice overexpressing AR showed a more pronounced inflammatory response in a cecal ligation and puncture model [5]. AR inhibition suppresses inflammatory disorders or immune responses in several other animal
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