Multistability in Macrophage Activation Pathways and Metabolic Implications

Abstract

Macrophages are innate immune cells with a dynamic range of reversible activation states including the classical pro-inflammatory (M1) and alternative anti-inflammatory (M2) states. Deciphering how macrophages regulate their transition from one state to the other is key for a deeper understanding of inflammatory diseases and relevant therapies. Common regulatory motifs reported for macrophage transitions, such as positive or double-negative feedback loops, exhibit a switchlike behavior, suggesting the bistability of the system. In this review, we explore the evidence for multistability (including bistability) in macrophage activation pathways at four molecular levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1, NF-KB/p50-p65) and M2 (STAT3, NF-KB/p50-p50) signaling pathways. Second, a switchlike behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, these changes impact metabolic gene expression, leading to switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis, and nitrogen metabolism. Fourth, metabolic changes are monitored by metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining signals promoting M1 or M2 activation. In conclusion, we identify bistability hubs as promising therapeutic targets for reverting or blocking macrophage transitions through modulation of the metabolic environment.

Macrophage phenotype transitions in a stochastic gene-regulatory network model

“…These phenotypes coincide with those identified in 15 . However, our results also indicate that the number of multi-stabile phenotypes (e.g., quad-stable) in stochastic systems is restricted to bi-and at most tri-stability, which is in accordance with the current literature [23][24][25] . The validity of this hypothesis would have a huge impact on our understanding of macrophage cells and needs to be confirmed.…”

Single-Cell Characterization of the Frizzled 5 (Fz5) Mutant Mouse and Human Persistent Fetal Vasculature (PFV)

“…Detail examination of their GO functional modules revealed that C5 expressed distinct genes of phosphate pentose ( Pgls and Taldo1 ) and purine salvage pathways ( Apert and Hprt ), an indicator M1 state ( Supplemental Data Sheet 2 ). 48 , 49 On the other hand, C30 and expressed genes were involved in de novo purine synthesis, such as Adss , Paics and Impdh2 , an indicator for M2 anti-inflammatory and phagocytic macrophages ( Supplemental Data Sheet 2 ). In addition, both clusters expressed glycolysis- and electron transfer chain-related proteins ( Supplemental Data Sheet 2 ).…”

“…The wild-type–specific macrophage C30 also leans toward M2-type, whereas the mutant C5 leans more toward M1 based on their metabolic signatures. 48 , 49 Therefore weaker M2-related phagocytic activity in the mutant vitreous might contribute to the unresolved cells.…”

Estimation of Early Postmortem Interval from Long Noncoding RNA Gene Expression in the Incised Cutaneous Wound: An Experimental Study

“…Macrophages have different phenotypes with unique functions during wound healing and their transition from M1-phenotype to M2-phenotype can be easily achieved by different inflammatory cytokines, including IL-4, IL-10, or IL-13, and various pathways of signal transduction, transcriptional and post-transcriptional regulatory networks, such as miRNAS, e.g., miR-27a-5p, let-7c-1-3p, and lncRNAS, e.g., lncFAO, lnc XIST, and lnc GAS5 [ 15 , 37 , 38 , 39 ] ( Figure 5 ).…”