Gbp1 Levels Fall with Age, Making Macrophages Less Helpful and More Harmful

Polarization is a categorization scheme for the cell state and behavior of the immune cells known as macrophages, which play a variety of roles in the body, ranging from the destruction of invaders and errant cells to assisting in regeneration. For the purposes of this discussion, the interesting states are M1, inflammatory and aggressive towards intruding pathogens, and M2, in which macrophages suppress inflammation and undertake other activities that aid in regeneration. Both have their roles to play, but many of the issues that arise in aged individuals are made worse by the increasing tendency of macrophages to exhibit the M1 polarization, even when it is unhelpful to do so.

While transient inflammation is a necessary part of the immune response, chronic inflammation (such as that produced by excess fat tissue or aging) is known to be disruptive to tissue maintenance and regeneration. This consideration of macrophages and inflammation is a thin slice of a much more complicated picture, but it is an important slice. While it is true that many other changes also take place in the aged immune system, here at least, researchers appear to have identified a regulatory protein that produces many of the problems exhibited by macrophages in older individuals. It will be interesting to see where the connections lead to from here, towards specific underlying forms of cell and tissue damage that cause aging. Note that the paper is as much focused on obesity as aging, but all of the relevant mechanisms examined appear in both circumstances.

Adipose tissue inflammation is a hallmark characteristic of obesity. Macrophages that infiltrate into adipose tissue and polarize to pro-inflammatory phenotype play a key role in obesity-associated adipose tissue inflammation and insulin resistance. Mechanistically, macrophages activated with the elevation of lipopolysaccharide (LPS) and IFNγ in obesity acquire an inflammatory M1 phenotype, characterized by increased production of pro-inflammatory cytokines and reactive oxygen species (ROS). These cytokines and ROS target adipocytes to further exacerbate adipose tissue inflammation and dysfunction.

Guanylate binding protein 1 (Gbp1) is a GTPase critical for innate immunity. This has been attributed to the role of Gbp1 in transporting autophagic machinery to the pathogen containing vacuoles (PCVs). Gbp1 expression can be largely induced by IFNγ in macrophages. Most previous studies primarily focused on the role of Gbp1 in regulating innate immunity of macrophages to defend against pathogen infections. Little is known about the involvement of Gbp1 in regulating polarization, metabolic programing, and cellular aging of macrophages.

In this study, we tested the hypothesis that Gbp1 plays a role in regulating immunometabolism and senescence of macrophages. We found that Gbp1 was mainly expressed in macrophages, but not adipocytes in response to IFNγ/LPS stimulation; Gbp1 expression was significantly decreased in inguinal white adipose tissue (iWAT) of high-fat diet (HFD)-fed and aged mice. We also observed that downregulation of Gbp1 in macrophages resulted in M1 polarization and impairment of mitochondrial respiratory function possibly via disrupting mitophagy activity. Moreover, macrophages with downregulated Gbp1 displayed dampened glycolysis and exhibited senescence-associated secretory phenotype (SASP). These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during aging.


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