“…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.
T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expression has been a trending topic in recent years due to its differential expression in a wide range of neoplasms. TIM-3 is one of the key immune checkpoint receptors that interact with GAL-9, PtdSer, HMGB1 and CEACAM1. Initially identified on the surface of T helper 1 (Th1) lymphocytes and later on cytotoxic lymphocytes (CTLs), monocytes, macrophages, natural killer cells (NKs), and dendritic cells (DCs), TIM-3 plays a key role in immunoregulation. Recently, a growing body of evidence has shown that its differential expression in various tumor types indicates a specific prognosis for cancer patients. Here, we discuss which types of cancer TIM-3 can serve as a prognostic factor and the influence of coexpressed immune checkpoint inhibitors, such as LAG-3, PD-1, and CTLA-4 on patients' outcomes. Currently, experimental medicine involving TIM-3 has significantly enhanced the anti-tumor effect and improved patient survival. In this work, we summarized clinical trials incorporating TIM-3 targeting monoclonal and bispecific antibodies in monotherapy and combination therapy and highlighted the emerging role of cell-based therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
