Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Abstract

Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

“…From the full set of gene expression in both conditions (see Material and Methods), we highlighted in red the upstream regulators, which are cytokines presented in both groups, while in yellow, only those expressed in the LPS/HI group are presented. In the present study, a total of 11 most significant genes from the cytokines cluster were selected in base of their function in microglia activation and inflammation [ 25 , 31 , 50 , 51 ]. For our study, the following cytokines were used: proinflammatory M1: IL1-beta , IL-6 , IL-12 , iNOS , and TNF-alpha and anti-inflammatory M2 : Arg-1 , CD206 , CCL11 , IL-4 , LIF , and TGF-beta [ 47 – 49 ].…”

“…After RNAseq, we focused on a gene set of microglia cytokines, as this clustered gene set showed the most significant genes upregulated in the vehicle/HI and LPS/HI groups, as illustrated in a volcano plot (Figures 2(a) and 2(b)). From the full set of gene expression in both conditions (see Material and Methods), we highlighted in red the upstream regulators, which are cytokines presented in both groups, while In the present study, a total of 11 most significant genes from the cytokines cluster were selected in base of their function in microglia activation and inflammation [25,31,50,51]. For our study, the following cytokines were used: proinflammatory M1: IL1-beta, IL-6, IL-12, iNOS, and TNF-alpha and anti-inflammatory M2: Arg-1, CD206, CCL11, IL-4, LIF, and TGF-beta [47][48][49].…”

Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain

“…The studies show the involvement of the CA1 region in the long-term recognition memory implementation [ 66 ]. Thus, increased neuronal activity in the CA1 region can provoke microglial activation [ 67 , 68 ] with subsequent degeneration of the neuronal tree due to hyperactivation and excitotoxicity [ 69 , 70 , 71 ]. The projections from layer II of the entorhinal cortex onto the neurons of the CA3 region, along with projections in the CA1 region, take part in the so-called temporoammonic pathway of sensory information entering the hippocampus.…”

“…The projections from layer II of the entorhinal cortex onto the neurons of the CA3 region, along with projections in the CA1 region, take part in the so-called temporoammonic pathway of sensory information entering the hippocampus. An increase in the microglial activity within the CA3 region seems to be a consequence of neuronal activation [ 68 ]. According to our data, an increase in the CD86-immunoreactivity (a marker of proinflammatory M1-type of microglia), is observed in CA1, CA3, and DG.…”

Nociception-dependent CCL21 induce dorsal root ganglia axonal growth via CCR7-ERK activation

“…Neurons alter their secretome when exposed to different stimuli and according to their physiological state. In that direction, neuronal activity has shown to modulate neuronal communication, including with microglia or with other neurons beyond classical neurotransmission (15)(16)(17). Nociceptor activity after axonal injury is normally associated with pathological neuropathic pain (18), despite that, some studies have started to uncover how nociception participates in the healing process, such as promoting skin or adipose tissue regeneration, as well as neovascularization (19)(20)(21).…”