Our Good Sister Lithium
It started as a bit of a joke between me and my cousin when we started calling lithium carbonate Lithium Aapa. Aapa, in Urdu-speaking Muslim households, is a term you use for an elder sister. An elder sister (or sibling, in general) is a confidant and the keeper of your secrets, and a guide who helps you navigate the world’s vicissitudes. If you think about it, Lithium, a beloved mood stabilizer with about a century of research behind it, does the same. No, for real. Read on.
So, Lithium Aapa purportedly works by inhibiting the metabolic enzyme glycogen synthase kinase (GSK3). GSK3 has multiple substrates and his its active site in many signal transductive pies, including those that govern neurotransmission. There are a lot of interesting data about Lithium Aapa’s timely and essential interventions in conditions like bipolar disorder and schizophrenia, but I shan’t go down that road right now. First of all, I speak neuro as a second language, at best. Secondly, this is an immunology blog, so we’re going to pivot towards Lithium Aapa’s filial affections towards CD8+ T cells.
This paper by Ma et al shows a whole new (to my knowledge) side to Lithium Aapa’s powers. In a mechanism that does not involve GSK3, this drug enables tumor-infiltrating CD8+ T cells to use lactate as a substrate for energy, thereby reversing their immunosuppression. Lactate can be a problem in the tumor microenvironment as it is known to “feed” famously immune suppressive Tregs and drive an anti-inflammatory phenotype in macrophages. It also turns down the volume on certain CD8 T cell transcription factors needed to keep the former activated and in fighting form.
Incidentally, the reason that Tregs can stand lactate-driven acidosis--hell, even thrive in it-- is because they possess a lactate transporter called MCT1 (monocarboxylate transporter 1). MCT1 allows Tregs to take up lactate and use it as an energy source. It’s interesting to see that Lithium Aapa uses the same-ish mechanism to revitalize CD8+ T cells. Ma et al’s data show that Lithium Aapa orchestrates MCT1’s move to the CD8s’ mitochondrial membranes, thus allowing those beleaguered cells to use lactate for energy and come back swinging. This is accomplished by rescuing Protein Kinase Cθ (PKCθ) signaling. The PKCs are custodians of immune homeostasis, and, due to Lithium Aapa’s intercession, the CD8s come alive seemingly to balance the suppressive effects of the Tregs in the picture.
We often call upon Lithium Aapa to bring balance to volatile moods that have us depressed or baleful or generally unable to keep it together. So there’s a certain beauty, wouldn’t you say, in how Lithium Aapa presides over immune homeostasis? You may think this fanciful, but equate immunosuppression in CD8s to a depressive episode: they can’t move, they can’t function and may actually die. At first blush, it may look like that all Lithium Aapa does for them is cheer them up, but it goes deeper than that. Lithium Aapa brings them back to being functional again. They are no longer suppressed (depressed) neither are they inappropriately inflammatory (manic), instead they are back and able to do their jobs once again. A solicitous sibling makes sure that you aren’t left behind and is willing to be your strength when you have none of your own. So, yeah, it was a bit of a joke at first, but Lithium Aapa ? You’re a gem.
