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. 2018 May 16;19(5):1473.
doi: 10.3390/ijms19051473.

The Cholinergic Anti-Inflammatory Response and the Role of Macrophages in HIV-Induced Inflammation

Free PMC article

The Cholinergic Anti-Inflammatory Response and the Role of Macrophages in HIV-Induced Inflammation

Manuel Delgado-Vélez et al. Int J Mol Sci. .
Free PMC article


Macrophages are phagocytic immune cells that protect the body from foreign invaders and actively support the immune response by releasing anti- and proinflammatory cytokines. A seminal finding revolutionized the way macrophages are seen. The expression of the neuronal alpha7 nicotinic acetylcholine receptor (α7-nAChR) in macrophages led to the establishment of the cholinergic anti-inflammatory response (CAR) in which the activation of this receptor inactivates macrophage production of proinflammatory cytokines. This novel neuroimmune response soon began to emerge as a potential target to counteract inflammation during illness and infection states. Human immunodeficiency virus (HIV)-infected individuals suffer from chronic inflammation that persists even under antiretroviral therapy. Despite the CAR's importance, few studies involving macrophages have been performed in the HIV field. Evidence demonstrates that monocyte-derived macrophages (MDMs) recovered from HIV-infected individuals are upregulated for α7-nAChR. Moreover, in vitro studies demonstrate that addition of an HIV viral constituent, gp120IIIB, to uninfected MDMs also upregulates the α7-nAChR. Importantly, contrary to what was expected, activation of upregulated α7-nAChRs in macrophages does not reduce inflammation, suggesting a CAR disruption. Although it is reasonable to consider this receptor as a pharmacological target, additional studies are necessary since its activity seems to differ from that observed in neurons.

Keywords: HIV; alpha7 acetylcholine receptor; cholinergic anti-inflammatory response; cholinergic receptors; inflammation; inflammatory response; macrophage.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
The cholinergic anti-inflammatory response (CAR) in normal and HIV-infected subjects. (A) During inflammation, the afferent vagus nerve recognizes microbial products (LPS) or cytokines (IL-6) that travel to the dorsal motor nucleus where they are interpreted and trigger an efferent response through the efferent branch of the vagus nerve. Accordingly, the efferent vagus nerve emerges from dorsal motor nucleus and innervates the celiac ganglion to release acetylcholine (ACh) that binds to α7-nAChRs in splenic neurons. Then, norepinephrine is release into the spleen via splenic nerve to activate β2-adrenergic receptors ChAT+ T lymphocytes which, in turn, secrete ACh that activates macrophage’s α7-nAChR, inhibiting the release of proinflammatory cytokines (i.e., TNF-α, IL-6, and IL-1β); (B) In HIV-infected subjects, the spleen and the CAR seem to be compromised and persistent inflammation is maintained. In fact, there is evidence demonstrating that addition of ACh does not decrease the production of proinflammatory cytokines in monocyte-derived macrophages despite elevated levels of α7-nAChR, suggesting a CAR disruption [107]. On the other hand, the α7-nAChR in macrophages could be exploited as a pharmacological option to treat inflammation by means of agonists, partial agonists, or positive allosteric modulators (PAMs).

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