More Research Needed on Cholinergic Anti-inflammatory Pathway Use in CTDs

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A look at the existing literature suggests more questions than answers remain when it comes to the potential use of the cholinergic anti-inflammatory pathway in connective tissue diseases (CTDs).

The intrinsic cholinergic anti-inflammatory pathway (CAP) may be a meaningful treatment opportunity for patients with connective tissue diseases (CTDs), but a new review article explains that a number of important questions remain.

Investigators from Tabriz University of Medical Science, in Iran, examined the latest research for a study published in Inflammopharmacology. The authors explained that there are a large number of CTDs, ranging from rheumatoid arthritis to systemic lupus erythematosus to Sjörgen’s syndrome.

One approach to treating these disorders has been through the use of anti-inflammatory agents, including the use of CAP to modulate chronic inflammation.

“Many different experimental and clinical models have been developed to evaluate the therapeutic significance of the CAP in CTDs,” the authors wrote. “On the other hand, an issue that is less emphasized in this regard is the presence of autonomic neuropathy in CTDs, which influences the efficiency of CAP in such clinical settings.”

It has been 2 decades since scientists first discovered the role of the cholinergic neural system in controlling inflammation. Since that time, investigators have identified alpha 7 nicotinic acetylcholine receptor α7nAChR, “which is expressed on immune cells, neurons, and many other non-neural cells,” as a key component of the pathway, they wrote.


Meanwhile, investigators have also found that vagus nerve stimulation can suppress tumor necrosis factor-alpha in wild-type mice, but not in α7nAChR-knockout mice.

“[I]t was concluded that α7nAChR is essential for the suppression of cytokine synthesis by CAP,” they wrote. “The molecular basis for CAP activation is the stimulation of α7nAChR by endogenous (eg, acetylcholine) or exogenous (eg, nicotine) ligands or many other natural or synthetic substances.”

Yet, those insights have not yet led to viable therapies.

“Due to the various physiological roles of these receptors, there are no discovered drugs that can be completely effective on α7nAChR without any side effects,” the authors wrote. However, they added, vagus nerve stimulation has been successfully used for therapeutic purposes.

They then outlined the role of the CAP pathway in various diseases, including rheumatoid arthritis and systemic sclerosis, saying there is a significant foundation of scientific literature, but more research is needed.

“Numerous studies support the future development of novel noninvasive bio-electronic treatment modalities for diseases currently treated with drugs,” they wrote.

The authors said investigators should undertake clinical trials to better understand the clinical efficacy of vagus nerve stimulation for CTDs, they said. Evidence also points to the possible involvement of the autonomic nerve system in the anti-arthritis action of the CAP, they added.

Meanwhile, several startups are looking into the use of implanted stimulators for autoimmune diseases.

“These data may portend favorable implications for the targeted treatment of chronic and debilitating human disorders, such as diabetes, arthritis, asthma, and inflammatory bowel disease, with α7-elective ligands,” the investigators wrote. “Also, it was shown that [vagus nerve stimulation] improves the peripheral immune milieu through CAP activation and ameliorates the severity of CTDs.”

In their conclusion, the investigators said α7nAChR remains a targetable element, although they said it remains controversial whether it positively or negatively correlates to rheumatoid arthritis.

“Therefore, the precise role of CAP in arthritis needs to be further investigated,” they wrote. “Delineating the complex influences of CAP would be critical in identifying the most appropriate methods to harness the therapeutic potential of this anti-inflammatory mechanism for the treatment of CTDs.”


Hajiasgharzadeh K, Khabbazi A, Mokhtarzadeh A, et al. Cholinergic anti-inflammatory pathway and connective tissue diseases. Inflammopharmacology. 2021;29(4):975-986. doi:10.1007/s10787-021-00812-z