Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance

Abstract

The efficient removal of apoptotic cells (ACs), a process termed as efferocytosis, is essential for immune homeostasis. While recent work has established an important interplay between efferocytosis and cellular metabolic changing, underlying mechanisms remain poorly known. Here, we discovered that pentose phosphate pathway (PPP) regulates tolerogenic ACs clearance and immune tolerance. ACs decreased levels of PPP-related genes and metabolites in macrophages. AG1, the agonist of PPP, increased the activity of PPP but greatly reduced macrophage phagocytosis of ACs and enhanced the inflammatory response during efferocytosis. miR-323-5p regulated the expression of PPP-related genes and its levels increased during efferocytosis. miR-323-5p inhibitor greatly promoted levels of PPP-related genes, reduced the macrophage phagocytosis of ACs, and increased inflammatory response during efferocytosis, suggesting that miR-323-5p was essential in regulating PPP activity and ACs clearance in macrophages. Correspondingly, the PPP agonist AG1 exacerbated the lupus-like symptoms in the AC-induced systemic lupus erythematosus (SLE) model. Our study reveals that regulating PPP-dependent metabolic reprogramming is critical for tolerogenic ACs phagocytosis and immune tolerance.

The role of efferocytosis‐fueled macrophage metabolism in the resolution of inflammation

“…In this latter setting, restoration of PPP activity in efferocytic macrophages blunted engulfment of apoptotic cells and stimulated pro-inflammatory cytokine production. 81 Consistent with these findings, a third study, that showed that PPP agonism reduced efferocytosis in vitro and aggravated autoimmune disease in a mouse model of SLE. 82 These findings suggest that PPP flux could be an important…”

“…While the oxidative phase of PPP was shown to support efferocytosis by generating NADPH in the setting of physiological hypoxia, 80 another study found that efferocytosis decreases PPP flux under normoxic conditions as a result of reduced expression of PPP‐related genes. In this latter setting, restoration of PPP activity in efferocytic macrophages blunted engulfment of apoptotic cells and stimulated pro‐inflammatory cytokine production 81 . Consistent with these findings, a third study, that showed that PPP agonism reduced efferocytosis in vitro and aggravated autoimmune disease in a mouse model of SLE 82 …”

Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress

“…A recent study by He et al (2022) showed that PCM4s downregulate PPP upon efferocytosis. They showed that a PPP agonist, AG1, reduces phagocytosis and enhances the inflammatory phenotype of PCM4s.…”

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

“…In addition to being involved in glycolysis, intracellular glucose is involved in the PPP by transforming into glucose 6-phosphate ( 191 ). A previous study suggested that efferocytosis and the PPP are mutually inhibitory ( 192 ). Moreover, a recent study demonstrated that reduced nicotinamide adenine dinucleotide phosphate from the PPP loop contributes to efferocytosis by macrophages under prolonged (chronic) physiological hypoxia ( 193 ).…”