Abstract: Systemic inflammation is often accompanied by adaptive responses mediated by the central nervous system, such as lack of motivation and attention, fatigue, malaise, irritation or even depression. This symptoms are summarized under the term “sickness behavior” (Dantzer et al., 2008). The inflammation-induced communication between the body and the brain uses neural as well humoral pathways, likely orchestrated by the major pro-inflammatory cytokines, such as interleukin (IL)-1α and β, tumor necrosis factor-α (TNF-α) and IL-6 (Dantzer et al., 2008). Interestingly, microglia, the main immune cells of the brain, sense peripheral inflammation as early as 5 hours after its induction by means of their intracellular Ca2+ signaling (Riester et al., 2020). Importantly, this change in Ca2+ signaling occurs long before the morphological activation of microglia, which usually takes place 24–48 hours after the induction of inflammation (Kozlowski and Weimer, 2012). Experimentally, the inflammation is often induced by the peripheral injection of lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria. Both the early LPS-mediated increase in microglial Ca2+ signaling and the delayed LPS-induced morphological activation of microglia were blocked in mutant mice lacking the NACHT-, LRR- and pyrin (PYD)-domain-containing protein 3 (NLRP3) inflammasome (Tejera et al., 2019; Riester et al., 2020). Moreover, the LPS-induced reactive astrocytosis, visualized by an increased expression of glial fibrillary acidic protein, was also absent in Nlrp3–/– mice (Tejera et al., 2019), thus identifying the NLRP3 inflammasome as a key player governing the brain’s immune response to peripheral inflammation.