“…TIM-3 is present in human microglia that are specifically localized to white matter [ 50 ]. LPS increases TIM-3 expression in murine microglia, and blocking its activity decreases their phagocytosis of apoptotic neurons [ 51 ]. Fig.…”
BackgroundMicroglia are the “professional” phagocytes of the CNS. Phagocytosis is crucial for normal CNS development and maintenance, but it can be either beneficial or detrimental after injury or disease. For instance, white matter damage releases myelin debris that must be cleared by microglia in order for re-myelination to occur. However, phagocytosis can also produce damaging reactive oxygen species (ROS). Furthermore, microglia can acquire pro-inflammatory (M1) or anti-inflammatory (M2) activation states that affect cell functions. Although microglia are exposed to a changing cytokine environment after injury or disease, little is known about the molecular and functional consequences. Therefore, we applied several microglial activation paradigms, with or without myelin debris. We assessed (i) gene expression changes reflecting microglial activation and inflammatory states, and receptors and enzymes related to phagocytosis and ROS production, (ii) myelin phagocytosis and production of ROS, and (iii) expression and contributions of several ion channels that are considered potential targets for regulating microglial behavior.MethodsPrimary rat microglia were exposed to cytokines, individually or sequentially. First, responses to individual M1 or M2 stimuli were compared: IFN-γ plus TNF-α (“I + T”; M1 activation), interleukin-4 (M2a/alternative activation), and interleukin-10 (M2c/acquired deactivation). Second, sequential cytokine addition was used to assess microglia repolarization and cell functions. The paradigms were M2a→M1, M2c→M1, M1→M2a, and M1→M2c.ResultsM1 stimulation increased pro-inflammatory genes, phagocytosis, and ROS, as well as expression of Kv1.3, KCa3.1, and Kir2.1 channels. M2a stimulation increased anti-inflammatory genes, ROS production, and Kv1.3 and KCa3.1 expression. Myelin phagocytosis enhanced the M1 profile and dampened the M2a profile, and both phagocytosis and ROS production were dependent on NOX enzymes and Kir2.1 and CRAC channels. Importantly, microglia showed some capacity for re-polarization between M1 and M2a states, based on gene expression changes, myelin phagocytosis, and ROS production.ConclusionsIn response to polarizing and re-polarizing cytokine treatments, microglia display complex changes in gene transcription profiles, phagocytic capacity, NOX-mediated ROS production, and in ion channels involved in microglial activation. Because these changes might affect microglia-mediated CNS inflammation, they should be considered in future experimental, pre-clinical studies.
“…TIM-3 is present in human microglia that are specifically localized to white matter [ 50 ]. LPS increases TIM-3 expression in murine microglia, and blocking its activity decreases their phagocytosis of apoptotic neurons [ 51 ]. Fig.…”
BackgroundMicroglia are the “professional” phagocytes of the CNS. Phagocytosis is crucial for normal CNS development and maintenance, but it can be either beneficial or detrimental after injury or disease. For instance, white matter damage releases myelin debris that must be cleared by microglia in order for re-myelination to occur. However, phagocytosis can also produce damaging reactive oxygen species (ROS). Furthermore, microglia can acquire pro-inflammatory (M1) or anti-inflammatory (M2) activation states that affect cell functions. Although microglia are exposed to a changing cytokine environment after injury or disease, little is known about the molecular and functional consequences. Therefore, we applied several microglial activation paradigms, with or without myelin debris. We assessed (i) gene expression changes reflecting microglial activation and inflammatory states, and receptors and enzymes related to phagocytosis and ROS production, (ii) myelin phagocytosis and production of ROS, and (iii) expression and contributions of several ion channels that are considered potential targets for regulating microglial behavior.MethodsPrimary rat microglia were exposed to cytokines, individually or sequentially. First, responses to individual M1 or M2 stimuli were compared: IFN-γ plus TNF-α (“I + T”; M1 activation), interleukin-4 (M2a/alternative activation), and interleukin-10 (M2c/acquired deactivation). Second, sequential cytokine addition was used to assess microglia repolarization and cell functions. The paradigms were M2a→M1, M2c→M1, M1→M2a, and M1→M2c.ResultsM1 stimulation increased pro-inflammatory genes, phagocytosis, and ROS, as well as expression of Kv1.3, KCa3.1, and Kir2.1 channels. M2a stimulation increased anti-inflammatory genes, ROS production, and Kv1.3 and KCa3.1 expression. Myelin phagocytosis enhanced the M1 profile and dampened the M2a profile, and both phagocytosis and ROS production were dependent on NOX enzymes and Kir2.1 and CRAC channels. Importantly, microglia showed some capacity for re-polarization between M1 and M2a states, based on gene expression changes, myelin phagocytosis, and ROS production.ConclusionsIn response to polarizing and re-polarizing cytokine treatments, microglia display complex changes in gene transcription profiles, phagocytic capacity, NOX-mediated ROS production, and in ion channels involved in microglial activation. Because these changes might affect microglia-mediated CNS inflammation, they should be considered in future experimental, pre-clinical studies.
“…Among the pharmacological tools to modulate TREM-2, Hsp60 is the main endogenous agonist of the microglial TREM-2 receptor [ 363 ]. TREM-2 binds PS, as already mentioned [ 345 ], as well as anionic carbohydrates, anionic bacterial products, and other phospholipids [ 364 , 365 ]. In a more specific manner, TREM-2 can be activated [ 366 ] or inhibited [ 367 ] by several antibodies.…”
Section: Triggering Receptors Expressed On Myeloid Cells 2 (Trem-2)mentioning
confidence: 94%
“…In the CNS, Tim-3 is expressed almost exclusively in microglia [ 195 , 341 , 344 - 346 ], with negligible expression in astrocytes [ 195 , 346 ]. In contrast, galectin-9 is produced by astrocytes and neurons [ 342 , 345 , 347 , 348 ] and, when released onto microglia, it induces TNF production [ 342 , 345 ]. Moreover, galectin-9 enhances poly(I:C)-induced microglial production of TNF and IL-6 [ 342 ].…”
Section: T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)mentioning
confidence: 99%
“…As a pharmacological tool to manipulate Tim-3 in microglia, galectin-9 has the caveat of being recognized by diverse receptors besides Tim-3 [ 349 - 351 ]. Fortunately, there are both activating and inhibiting Tim-3 antibodies that can be more specific than galectin-9 [ 341 , 345 , 346 ]. As far as we are aware, there are no studies regarding the role of Tim-3 in neural network function.…”
Section: T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)mentioning
confidence: 99%
“…In a more specific manner, TREM-2 can be activated [ 366 ] or inhibited [ 367 ] by several antibodies. TREM-2 activation leads to the induction of a phagocytic microglial state [ 345 ] and the promotion of microglial survival [ 345 ]. As for its influence on neural network function, the absence of DAP12 leads to reduced GluR1 and GluR2 levels in the post-synaptic density, whereas it increases the inward rectification of synaptic AMPARs [ 324 ] and increases the AMPA/NMDA ratio [ 368 ].…”
Section: Triggering Receptors Expressed On Myeloid Cells 2 (Trem-2)mentioning
BackgroundMicroglia are the resident immunocompetent cells of the CNS and also constitute a unique cell type that contributes to neural network homeostasis and function. Understanding microglia cell-signaling not only will reveal their diverse functions but also will help to identify pharmacological and non-pharmacological tools to modulate the activity of these cells.MethodsWe undertook a search of bibliographic databases for peer-reviewed research literature to identify microglial activators and their cell-specificity. We also looked for their effects on neural network function and dysfunction.ResultsWe identified several pharmacological targets to modulate microglial function, which are more or less specific (with the proper control experiments). We also identified pharmacological targets that would require the development of new potent and specific modulators. We identified a wealth of evidence about the participation of microglia in neural network function and their alterations in pathological conditions.ConclusionThe identification of specific microglia-activating signals provides experimental tools to modulate the activity of this heterogeneous cell type in order to evaluate its impact on other components of the nervous system, and it also helps to identify therapeutic approaches to ease some pathological conditions related to microglial dysfunction.
BackgroundBlocking of Tim‐3 exerts therapeutic effects in a series of ischemia‐reperfusion injury (IRI).MethodsIn this work, a cross‐clamped aortic arch was conducted to establish SCIRI rat model. Besides, rat spinal microglia was subjected to OGD/R to mimic I/R‐like conditions in vitro. The in vivo and in vitro therapeutic effects of Tim‐3 antibody in SCIRI were investigated from these aspects: neuronal apoptosis, neuroinflammation, microglia activation, and polarization.ResultsIt was verified that Tim‐3 was highly expressed in spinal cord tissues of SCIRI rats and blocking of Tim‐3 attenuated SCIRI‐induced pathological injury, neuronal apoptosis, neuroinflammation, and microglia activation (M1 polarization). In addition, it was verified that Tim‐3 was highly expressed in OGD/R‐treated rat spinal microglia and blocking of Tim‐3 attenuated OGD/R‐induced inflammation and spinal microglia activation (M1 polarization).ConclusionsTim‐3 antibody can exert therapeutic effects in SCIRI through inhibiting neuroinflammation and promoting microglia polarization from M1 to M2 phenotype.
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