Caffeine Has Different Immunomodulatory Effect on the Cytokine Expression and NLRP3 Inflammasome Function in Various Human Macrophage Subpopulations

Abstract

Besides its well-known psychoactive effects, caffeine has a broad range of actions. It regulates several physiological mechanisms as well as modulates both native and adaptive immune responses by various ways. Although caffeine is assumed to be a negative regulator of inflammation, the effect on the secretion of pro- and anti-inflammatory cytokines is highly controversial. Macrophages are major mediators of inflammatory responses; however, the various subpopulations develop different effects ranging from the initiation to the resolution of inflammation. Here we report a comparative analysis of the effect of caffeine on two subpopulations of human monocyte-derived macrophages differentiated in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in M-MΦs and GM-MΦs, respectively. We showed that although TNF-α secretion was downregulated in both LPS-activated MΦ subtypes by caffeine, the secretion of IL-8, IL-6, and IL-1β as well as the expression of Nod-like receptors was enhanced in M-MΦs, while it did not change in GM-MΦs. We showed that caffeine (1) altered adenosine receptor expression, (2) changed Akt/AMPK/mTOR signaling pathways, and (3) inhibited STAT1/IL-10 signaling axis in M-MΦs. We hypothesized that these alterations play an important modulatory role in the upregulation of NLRP3 inflammasome-mediated IL-1β secretion in LPS-activated M-MΦs following caffeine treatment.

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model

“…According to our results, CAF down-regulated LPS-induced TNF expression also in the ovine ChP. Interestingly, opposite to IL-1β secretion, CAF abolished TNFα synthesis in both M1 and M2 macrophages as well as in monocytes [54]. Likewise, the in vitro study on LPS-stimulated human whole blood demonstrated that concentrations of CAF relevant to human consumption consistently decreased TNFα concentration in blood and that this effect was mediated by the cAMP/protein kinase A pathway [58].…”

“…Moreover, the same study [54] also showed that there were important differences in the time of cell response to CAF action. In M2 macrophages CAF enhanced IL-1β secretion as early as 6 h after LPS administration, while in monocytes only after 12 h [54]. Therefore, the differences in the response of the hypothalamus and ChP to CAF may be due to the different cellular compositions, locations, and nature of these structures.…”

“…According to Kovács et al [54], CAF enhanced the expression of IL-1β, in the subset of human M2 macrophages, whereas it did not influence the expression of IL1-β in the subset of M1 macrophages and mouse BMDM. Moreover, the same study [54] also showed that there were important differences in the time of cell response to CAF action. In M2 macrophages CAF enhanced IL-1β secretion as early as 6 h after LPS administration, while in monocytes only after 12 h [54].…”

Adenosine receptor signalling in Alzheimer’s disease

“…A 2A R activation stimulates sustained NLRP3 inflammasome activity and the production of proinflammatory cytokines (e.g. IL-1β) in macrophages and primary microglia [232][233][234][235]. Notably, in preclinical models of hypoxic-ischemia and autoimmune encephalomyelitis, caffeine inhibited NLRP3 inflammasome activation and microglial activation to confer neuroprotection and attenuate disease pathology [236,237].…”

SDSS ameliorates cerebral ischemia/reperfusion injury by inhibiting CLIC4/NLRP3 inflammasome-mediated endothelial cell pyroptosis

“…NLRP3 in ammasome activation may be regulated by a wide range of factors [34], although its mechanism is unclear. For example, it occurs when intracellular ions are disturbed, such as an increase in K + e ux [35] or Ca 2+ in ux [36] due to a variety of stimulis.…”