Inspired by Titiz et al 2024.[1]
SCs – Schwann cells
IF – impact factor
AMA – abdominal mechanical allodynia
PMA – periorbital mechanical allodynia
HMA – hind paw mechanical allodynia
C5a – a small soluble pro-inflammatory peptide that functions as an anaphylatoxin
DAMPs – damage-associated molecular patterns
C5aR1 – C5a receptor 1
GPCR – G protein-coupled receptor
NLRP1 – NOD-like receptor family, pyrin domain containing 1
IL-1β – interleukin 1 beta
TRPA1 – transient receptor potential ankyrin 1
NLRP3 – NOD-like receptor family, pyrin domain containing 3
AD – Alzheimer’s disease
IBD – inflammatory bowel disease– key to acronyms
This paper in Nature Communications (IF 14.7) comes from a research group in Florence, which happens to be just 100km down the road from where I am starting to write this blog in Bologna airport.
I was attracted by the word inflammasome in the title of the paper and the fact that it was in a big journal. Those of you who attended the BMAS expert forum at the WFAS 2024 meeting in London (Heathrow) will have heard an interesting talk from Dr Miltiades (Miltos) Karavis on neuroinflammatory disorders and the possible ubiquitous role of acupuncture. The key commonality across the disorders was the role of inflammasomes.
Inflammasomes are multiprotein complexes found in the cytoplasm of mainly phagocytic immune cells, but they can appear in some other cells, such as those listed below. They are responsible for the rapid initiation of inflammation as part of innate defences by activating cytokines and pyroptosis (a form of programmed cell death that enhances inflammation and immune responses).
Immune cells with inflammasomes
Macrophages – key players in inflammasome activation, especially during infection and tissue damage.
Dendritic cells – use inflammasomes to modulate immune responses and communicate with other immune cells.
Neutrophils – can express functional inflammasomes, although their role may be less studied compared to macrophages.
Non-immune cells with inflammasomes
Epithelial cells – found in the gastrointestinal tract, respiratory system, and skin, where they act as the first line of defence against pathogens.
Endothelial cells – can express inflammasomes in response to infections or damage, playing a role in vascular inflammation.
Fibroblasts – may contribute to chronic inflammation and fibrotic diseases through inflammasome signalling.
Adipocytes – inflammasome activation in fat cells is linked to metabolic inflammation, such as in obesity and type 2 diabetes.
Neuronal cells – although rare, some neurons and glial cells (eg astrocytes, microglia) can express inflammasomes, implicated in neuroinflammatory diseases like Alzheimer’s and Parkinson’s.
This is a complex paper using rather sophisticated methods to reveal the mechanistic steps that lead from the development of endometriosis to both increased regional (AMA here) as well as worsening migraine headaches (PMA here) and widespread pain (HMA here).
Endometriosis activity leads (in both female mice and women) to an increase in plasma C5a – a complement factor that is part of the innate immune system. The blood and cellular debris from endometriotic lesions create DAMPs, which activate immune cells, generate inflammation and thus complement activation.
C5aR1 on Schwann cells is a GPCR that activates the NLRP1 inflammasome to activate the cytokine IL-1β, which in turn attracts macrophages whose oxidative burst stimulates TRPA1 receptors on both SCs and the adjacent neurones.
TRPA1 activation on neurones results in lowered mechanical thresholds (tenderness) and this occurs both local to the endometriotic lesions but also throughout the rest of the body since C5a is increased in the circulation.
But what about the role of acupuncture I heard you cry? Well, there was no mention of acupuncture in this particular paper, but Miltos had said acupuncture influences the inflammasomes, so I looked up some papers on PubMed and asked ChatGPT. The latter confirmed that acupuncture can modulate inflammasome activity and reduce inflammation but it was somewhat more difficult to actually find the papers to support this on PubMed.
The most suitable ones I found were both from China. One implicated inhibition of the NLRP1 inflammasome in mediating the positive effects of acupuncture in an AD mouse model.[2] The other implicated inhibition of the NLRP3 inflammasome in mediating the positive effects of acupuncture in a mouse model of IBD.[3]
I will try to explain this story in more detail at the Wednesday blog webinar.
References
1 Titiz M, Landini L, Souza Monteiro de Araujo D, et al. Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis. Nat Commun. 2024;15:10142. doi: 10.1038/s41467-024-54486-6
2 Zhang T, Guan B, Tan S, et al. Bushen Huoxue Acupuncture Inhibits NLRP1 Inflammasome-Mediated Neuronal Pyroptosis in SAMP8 Mouse Model of Alzheimer’s Disease. Neuropsychiatr Dis Treat. 2021;17:339–46. doi: 10.2147/NDT.S279304
3 Chen Y, Cai M, Shen B, et al. Electroacupuncture at Zusanli regulates the pathological phenotype of inflammatory bowel disease by modulating the NLRP3 inflammasome pathway. Immun Inflamm Dis. 2024;12:e1366. doi: 10.1002/iid3.1366
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