Abstract
Aging disrupts the maintenance of liver homeostasis, which impairs hepatocyte regeneration and aggravates acute liver injury (ALI), ultimately leading to the development of acute liver failure (ALF), a systemic inflammatory response, and even death. Macrophages influence the progression and outcome of ALI through the innate immune system. However, it is still unclear how macrophages regulate ALI during aging. The variation in macrophage autophagy with aging and the influence on macrophage polarization and cytokine release were assessed in BMDMs in vitro. Then, after BMDMs subjected to several treatments were intravenously or intraperitoneally injected into mice, thioacetamide (TAA)-induced ALI (TAA-ALI) was established, and its effects on inflammation, injury, and mortality were assessed. We found that aging aggravated the liver injury, along with increases in the levels of proinflammatory mediators, presenting a senescence-associated secretory phenotype (SASP), which promoted macrophage polarization to the M1 phenotype. In addition, autophagy levels decreased significantly in aged mice, which was ascribed to ATG5 repression during aging. Notably, enhancing autophagy levels in aged BMDMs restored macrophage polarization to that observed under young conditions. Finally, autophagy restoration in aged BMDMs enhanced the protective effect against TAA-ALI, similar to M2 macrophages induced by IL-4. Overall, we demonstrated that the influence of aging on macrophage polarization is an important aggravating factor in TAA-ALI, and the autophagy in macrophages is associated with the aging phenotype.
Highlights
As the main site of nutrient and toxin metabolism and a barrier to complex pathogenic factors from the external environment [1], the liver can be damaged by multiple toxins and their metabolites, but it usually regenerates after moderate injury due to its remarkable regeneration capacity [2]
We found that aging aggravated the liver injury, along with increases in the levels of proinflammatory mediators, presenting a senescence-associated secretory phenotype (SASP), which promoted macrophage polarization to the M1 phenotype
We demonstrated that the influence of aging on macrophage polarization is an important aggravating factor in TAA-acute liver injury (ALI), and the autophagy in macrophages is associated with the aging phenotype
Summary
As the main site of nutrient and toxin metabolism and a barrier to complex pathogenic factors from the external environment [1], the liver can be damaged by multiple toxins and their metabolites, but it usually regenerates after moderate injury due to its remarkable regeneration capacity [2]. Level, the content of the proinflammatory factors TNF-α, IL-1β, and Exploring aging-related polarization mechanisms is crucial to IL-6 in the peripheral blood of aged mice increased, suggesting an recognize the role of macrophages in ALI, and interventions anabatic SASP in aged mice during TAA-ALI (Fig. 2G). ATG5 knockout mice showed higher IL-1α and IL-1β levels and GFP-LC3) fusion protein was transfected into BMDMs from remarkable recruitment of macrophages and neutrophils, which young and aged mice to evaluate autophagic flux by measuring are associated with aggravated liver injury [18]. Thioacetamide (TAA), which is metabolized to its S-oxide (TASO) lower than that of BMDMs from young mice (young BMDMs), and further to S, S-dioxide (TASO2) through the biological which paralleled the impaired autophagy indicated by the oxidation of cytochrome P450 (CYP) 2E1 in vivo [19], is a classic reduced autophagosomes (Fig. 3B, C) and LC3 puncta (Supplehepatotoxic agent that induces acute or chronic liver inflamma- mentary Fig. S1A) in the cells after LPS treatment. We further explored the influence of aging on the polarization phenotype of macrophages after LPS treatment, and autophagy-related proteins were detected by immunofluor-
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