Perhaps one of the rarer joys in the life of a graduate student, along with scoring a publication, is going on a date. The sun sits low in a way that it only does in Fargo—duplicitously, making one question whether it were gloaming or dawning, and here I am at one of our more upscale eateries with a compelling companion who had been introduced to me via a mutual friend. Those of you rolling your eyes at the idea of a set-up, know that when you are the apex of a scalene triangle involving a rigorously demanding biochemistry course and recalcitrant mice, you will learn to take what you get. And, in my case, what I’d gotten was quite diverting indeed!
“So, Cody told me that you worked with mice, or is that what you secretly call your co-workers?” my date asks, grinning.
I laugh throatily, my cheeks flushed with the fine Shiraz that we’d been sharing. “In a sense, the mice are my co-workers, as would be the story of every immunologist-in-the making!”
“Ah, immunobiology,” my vocal performance major friend wonders. “It is a very fashionable field these days.”
“If it’s fashionable, it’s because it’s cosmopolitan. Every disorder has an immunological basis. Every!” I declare.
“Is that jingoism I see in your eyes?” The flirtatious mockery is evident. It makes me blush—a terrible consequence for men of my complexion.
“I’m not crazy, I promise!” I say, deliberately injecting a manic edge in my voice.
“Oh, I don’t know…you speak in tongues and abbreviations, and recreationally kill mice….”
“Hey, now! ‘Inflammasome’ is a real word!”
“Sure, sure! It sounds nasty! More wine?”
“It is NOT nasty! It is beautiful!” I cry.
Then something inexplicable happens: I am offended by how quickly the inflammsome has been dismissed. The idea of the inflammasome is a recent one, but it goes a long way in informing the complexity of the innate immune response. As microbial products and/or damage-associated molecular patterns are released from cells, they are recognized by inflammasomes. The inflammasomes, in turn, mediate the production of inflammatory cytokines like IL-1β and IL-18. Inflammation is not to be taken lightly, given how beautifully it is regulated by inflammasomes as this April’s Nature Immunology apprises.
Back at the restaurant, I find myself fishing out a pen from the back-pocket of my pants and grabbing a napkin from the table. Upon this napkin, I draw a blob. “Now this is a macrophage, okay? And the inflammasome is this complex of proteins inside it.” I draw another blob within the blob.
“Hmmmm.” My date drones.
“So, there’s this enzyme called AMP-kinase, right? Which inhibits cholesterol synthesis. I think we agree that that’s nice work, if you can get it, and, if your diet is heavy in fats, that becomes a BIG if, because long-chain fatty acids inhibit the enzyme itself.”
“I see.” My date nods, as I draw wiggly lines around the blob to represent long-chain fatty acids.
“Now because fatty acid metabolism happens in the mitochondria…”
“The Powerhouse of the cell!” My date grasps onto something familiar. “Did you just roll your eyes at me?”
“Oh, no.” I aver quickly. “But, anyway, so fatty acid metabolism, like beta-oxidation and ketogenesis, is not happening so the mitochondria start getting degraded by the cell, and the components of the dead mitochondria activate this guy!” I quip, drawing an arrow from my bean-shaped blob supposed to represent a mitochondrion to the ellipsoidal entity supposed to be the inflammasome. The NLRP inflammasome, to be precise, but I wasn’t going to be elitist. Not on a date! Heaven forfend!
“Right…” My date takes a deep draw from the wine-glass.
“Exactly! So once the inflammasome is activated, it produces an incendiary chemical called IL-1β. Now, this IL-1β engages with its receptor on insulin producing beta-cells, and then signalling happens!”
“So, the coming together of a receptor and a molecule causes signalling, eh?” My date suggests huskily.
“Yes! In this case, that signalling leads to cell death. The protein in question, NF-κB they call it, is a many splendour’d thing, but, in conjunction with MAP Kinases, it’s a self-destruct button.” I draw a cloud of smoke on the napkin around the blob supposed to signify a pancreatic beta cell.
“So, you have all these beta cells being killed by immunological phenomena caused by poor choices in gourmandizing, et voila! No insulin is produced, and you have Type II diabetes!”
“This conversation goes so well with this Hollandaise sauce here!” My date titters good-naturedly. “That was fascinating, Akshat.”
“I’m glad you think so!”
“But, not very romantic…”
There is a moment of silence as I busy myself with my Zuccoti.
“Perhaps, we should do a shot.” My companion suggests with a chortle.
P.S. To read more about inflammasomes and their roles in metabolic disorders, I strongly recommend a fantastic piece by Haitao Wen et al in this April’s Nature Immunology: “A role for the NLRP3 inflammasome in metabolic diseases- did Warburg miss inflammation?”