This 2020 study investigated genes and signaling pathways for inflammatory memory:

“Fibroblast-like synoviocytes (FLS) play a critical role in pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment.

Sustained activated genes established pro-inflammatory signaling components known to act at multiple levels of NF-κB, STAT and AP-1 signaling cascades. Sustained repressed genes included critical mediators and targets of the BMP [bone morphogenic protein] signaling pathway.

We identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation.

FLS are synovial tissue-resident and specialized mesenchymal cells critical for homeostasis. Key features of these cells during homeostasis include the production of extracellular matrix components and providing nutrients to the synovial fluid. Healthy synovium is composed of multiple layers of FLS, which forms the synovial lining and sublining through cell–cell contacts.

Inflammatory and pro-resolving mediators are tightly regulated to maintain normal synovium functioning. However, in inflammatory and autoimmune diseases such as rheumatoid arthritis, an imbalance between these signals causes homeostasis disruption leading to synovial tissue damage, cartilage destruction and bone degeneration.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679373/ “Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory”

These researchers described a positive feedback loop that kept rheumatoid arthritis in place. No feedback diagram or explanation of what sustained a disease condition other than to say:

“Gene expression changes induced by short-term tumor necrosis factor-alpha (TNF-α) treatment were largely sustained in the FLS exposed to chronic inflammation.”

Okay – then what upstream signals sustained TNF-α? What would it take to interrupt that feedback loop? What initiated it?

Studies usually substantiate effects by also developing evidence for causes of opposite effects and of no effects. This study investigated neither reversibility nor no effect, and instead stated:

“Multiple signaling networks are irreversibly modified due to TNF-α-mediated long-term epigenetic and transcriptomic reprogramming. We speculate that sustained repression of BMP signaling may be critically required to ensure the persistently transformed phenotype of RA FLS.”

No evidence was offered for “irreversibly modified.” Anyway, that didn’t fit with:

“We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.”

Enduring epigenetic memories? Or continuous toxic stimulation? provided another perspective: “Enduring epigenetic effects may be symptoms rather than causes when toxic conditions persist.”

Been on a Steely Dan kick lately. Probably due to this year’s Royal Scam: