ST36 EA and T cells in sepsis

Inspired by Lv et al 2022.[1]

EA – electroacupuncture
LPS – lipopolysaccharide (derived from bacterial cell membranes)
TNFα – tumour necrosis factor alpha
IL-1β – interleukin 1 beta
IL-6 – interleukin 6

key to acronyms

I spotted this paper because the title promised something new in the story of EA mediated survival in sepsis and because Luis Ulloa appeared on the list of authors. Luis ran the lab that first reported a reduced mortality related to the use of ST36 EA in an animal model of sepsis in 2014.[2] They had been using direct vagal nerve stimulation in his lab until an acupuncturist in a conference in Mexico suggested trying EA, and the rest is history.

Luis Ulloa’s lab was first to report reduced mortality in a mouse model of sepsis after ST36 EA

This paper repeats a very similar procedure using EA applied to ST36 on 3 consecutive days prior to the induction of sepsis with intraperitoneal injection of LPS at 4mg/kg. The dose of LPS had be tested such that the LPS mice would only survive to 24–48 hours after the injection.

The EA was applied at 10Hz and 0.1mA for 30 minutes. The frequency is consistent with previous research,[2,3] and may be optimal for autonomic modulation (Longhurst, personal communication). The current seems a bit low, but we are not told the pulse width, and this can make quite a difference. Previously, a current as low as 0.5mA at a pulse width of 50μs has demonstrated effects in sepsis.[3]

I recall asking Prof Jing from Beijing about using 0.1mA EA in a paper last year.[4] She told me that the animals would not tolerate 0.2mA, and it turned out that they were using a pulse width of 1ms (ie 1000μs). Most devices do not have controls finer than 0.1mA steps, so it would be preferable to use a pulse width between 50μs and 200μs so that the control of current has a broader range of possible steps of 0.1mA.

All the animals in the LPS group died within 48 hours, but in the EA+LPS group 50% survived. Pathology in the lung and small intestine was reduced by around 50%, and all the usual cytokines were reduced.

I was interested to note that TNFα and IL-1β rose early in the inflammatory process (within 2 hours) and EA could attenuate this early rise; however, the rise of IL-6 (a key secondary cytokine) was not attenuated by EA until later (12 hours). The implication here is that EA can prevent the initial rise of the key early pro-inflammatory cytokines and therefore reduce or prevent the development of a cytokine storm. We have been hearing a lot about the lethality of the latter in severe cases of COVID, but not so much about the subsequent effect on T lymphocyte apoptosis and pyroptosis.

Pyroptosis is a form of apoptosis (programmed cell death) related to intense inflammation. In sepsis, the intensity of the inflammation results in a secondary drop in T lymphocytes, and certain splenic T lymphocytes are required for mediating part of the vagal anti-inflammatory reflex. Luckily the lymphopenia is secondary, so EA can prevent this by attenuating the early rise of excess cytokines.

Early ST36 EA can prevent secondary lymphopenia in sepsis

Finally, to complete the story, nude mice lacking T lymphocytes were also used, and in them EA had no effect on the rise in TNFα after LPS injection. This means that if we are to use EA at ST36 in sepsis or severe inflammatory conditions, we would be best to ensure that we get in early and apply it before splenic T lymphocytes get the chance to check out of the party!

References

1          Lv Z-Y, Shi Y-L, Bassi GS, et al. Electroacupuncture at ST36 (Zusanli) Prevents T-Cell Lymphopenia and Improves Survival in Septic Mice. J Inflamm Res 2022;15:2819–33. doi:10.2147/JIR.S361466

2          Torres-Rosas R, Yehia G, Peña G, et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 2014;20:291–5. doi:10.1038/nm.3479

3          Liu S, Wang Z, Su Y, et al. A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature 2021;598:641–5. doi:10.1038/s41586-021-04001-4

4          Zhang Z, Yu Q, Zhang X, et al. Electroacupuncture regulates inflammatory cytokines by activating the vagus nerve to enhance antitumor immunity in mice with breast tumors. Life Sci 2021;272:119259. doi:10.1016/j.lfs.2021.119259

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Declaration of interests MC