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24 pages, 4228 KiB

Open AccessArticle

A Model of iPSC-Derived Macrophages with TNFAIP3 Overexpression Reveals the Peculiarities of TNFAIP3 Protein Expression and Function in Human Macrophages

by Olga Sheveleva, Elena Protasova, Tatiana Nenasheva, Nina Butorina, Victoria Melnikova, Tatiana Gerasimova, Olga Sakovnich, Alexander Kurinov, Elena Grigor’eva, Sergey Medvedev and Irina Lyadova

Int. J. Mol. Sci. 2023, 24(16), 12868; https://doi.org/10.3390/ijms241612868 - 16 Aug 2023

Cited by 1 | Viewed by 1508

Abstract

Macrophages play a crucial role in the development and control of inflammation. Understanding the mechanisms balancing macrophage inflammatory activity is important to develop new strategies for treating inflammation-related diseases. TNF-α-induced protein 3 (TNFAIP3, A20) is a negative regulator of intracellular inflammatory cascades; its [...] Read more.

Macrophages play a crucial role in the development and control of inflammation. Understanding the mechanisms balancing macrophage inflammatory activity is important to develop new strategies for treating inflammation-related diseases. TNF-α-induced protein 3 (TNFAIP3, A20) is a negative regulator of intracellular inflammatory cascades; its deficiency induces hyper-inflammatory reactions. Whether A20 overexpression can dampen macrophage inflammatory response remains unclear. Here, we generated human-induced pluripotent stem cells with tetracycline-inducible A20 expression and differentiated them into macrophages (A20-iMacs). A20-iMacs displayed morphology, phenotype, and phagocytic activity typical of macrophages, and they displayed upregulated A20 expression in response to doxycycline. A20 overexpression dampened the A20-iMac response to TNF-α, as shown by a decreased expression of IL1B and IL6 mRNA. A dynamic analysis of A20 expression following the generation of A20-iMacs and control iMacs showed that the expression declined in iMacs and that iMacs expressed a lower molecular weight form of the A20 protein (~70 kDa) compared with less differentiated cells (~90 kDa). A low-level expression of A20 and the predominance of a low-molecular-weight A20 form were also characteristic of monocyte-derived macrophages. The study for the first time developed a model for generating macrophages with an inducible expression of a target gene and identified the peculiarities of A20 expression in macrophages that likely underlie macrophage preparedness for inflammatory reactivity. It also suggested the possibility of mitigating inflammatory macrophage responses via A20 overexpression. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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15 pages, 3572 KiB

Open AccessArticle

Over-Expression of p190RhoGEF Regulates the Formation of Atherosclerotic Plaques in the Aorta of ApoE^−/− Mice via Macrophage Polarization

by So-Yeon Choi, Eun-Bi Lee, Jee-Hae Kim and Jong Ran Lee

Int. J. Mol. Sci. 2023, 24(16), 12785; https://doi.org/10.3390/ijms241612785 - 14 Aug 2023

Cited by 1 | Viewed by 1243

Abstract

The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF [...] Read more.

The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF could affect atherosclerotic plaque formation in mouse aortae. For that purpose, transgenic (TG) mice over-expressing p190RhoGEF were cross-bred with atherosclerosis-prone apolipoprotein E (ApoE)^−/− mice to obtain p190RhoGEF-TG mice with ApoE^−/− backgrounds (TG/ApoE^−/−). Aortic plaque formation was significantly increased in TG/ApoE mice^−/− at 30 to 40 weeks of age compared to that in ApoE^−/− mice. Serum concentrations of inflammatory cytokines (IL-6 and TNF-α) were greater in TG/ApoE^−/− mice than in ApoE^−/− mice at ~40 weeks of age. Furthermore, TG/ApoE^−/− mice had a greater proportion of peritoneal macrophages within the M1 subset at 30 to 40 weeks of age, together with higher production of inflammatory cytokines and stronger responses to bacterial lipopolysaccharide than ApoE^−/− mice. Collectively, these results highlight a crucial role of enhanced p190RhoGEF expression in atherosclerosis progression, including the activation of pro-inflammatory M1 macrophages. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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14 pages, 1716 KiB

Open AccessArticle

Comparative Analysis of Fcγ and Complement Receptors Presence on Monocytes in Pulmonary Sarcoidosis and Tuberculosis

by Marlena Typiak, Piotr Trzonkowski, Monika Skotarczak and Anna Dubaniewicz

Int. J. Mol. Sci. 2023, 24(11), 9713; https://doi.org/10.3390/ijms24119713 - 3 Jun 2023

Cited by 1 | Viewed by 1277

Abstract

Sarcoidosis (SA) is a granulomatous disorder, which mostly affects the lungs. Its clinical characteristics resemble tuberculosis (TB), but its treatment is different. The etiology of SA is unknown; however, mycobacterial antigens were proposed as environmental factors in its development. Due to previously revealed [...] Read more.

Sarcoidosis (SA) is a granulomatous disorder, which mostly affects the lungs. Its clinical characteristics resemble tuberculosis (TB), but its treatment is different. The etiology of SA is unknown; however, mycobacterial antigens were proposed as environmental factors in its development. Due to previously revealed immunocomplexemia with mycobacterial antigens in the blood of our SA but not TB patients, and in the search for biomarkers for differential diagnosis of the two disorders, we studied the phagocytic activity of monocytes from both patients’ groups with flow cytometry. With the use of this method, we also analyzed the occurrence of receptors for IgG (FcγR) and complement components (CR) at the surface of these monocytes, responsible for phagocytosis of immunocomplexes. We revealed a higher phagocytic activity of monocytes in both disorders, but an increased frequency of monocytes with FcγRIII (CD16) and decreased with CR1 (CD35) receptor in the blood of SA vs. TB patients. With regard to our other genetic study on FcγRIII variants in SA and TB, this may account for the decreased clearance of immunocomplexes and different immune responses in the two diseases. Thus, the presented analysis not only sheds light on the pathomechanisms of SA and TB but may also support their differential diagnosis. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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36 pages, 6188 KiB

Open AccessArticle

RNA-Seq Reveals Sex Differences in Gene Expression during Peripheral Neuropathic Inflammation and in Pain Relief from a COX-2 Inhibiting Theranostic Nanoemulsion

by Brooke Deal, Katherine Phillips, Caitlin Crelli, Jelena M. Janjic and John A. Pollock

Int. J. Mol. Sci. 2023, 24(11), 9163; https://doi.org/10.3390/ijms24119163 - 23 May 2023

Cited by 5 | Viewed by 2659

Abstract

Given decades of neuroinflammatory pain research focused only on males, there is an urgent need to better understand neuroinflammatory pain in females. This, paired with the fact that currently there is no long-term effective treatment for neuropathic pain furthers the need to evaluate [...] Read more.

Given decades of neuroinflammatory pain research focused only on males, there is an urgent need to better understand neuroinflammatory pain in females. This, paired with the fact that currently there is no long-term effective treatment for neuropathic pain furthers the need to evaluate how neuropathic pain develops in both sexes and how it can be relieved. Here we show that chronic constriction injury of the sciatic nerve caused comparable levels of mechanical allodynia in both sexes. Using a COX-2 inhibiting theranostic nanoemulsion with increased drug loading, both sexes achieved similar reduction in mechanical hypersensitivity. Given that both sexes have improved pain behavior, we specifically explored differential gene expression between sexes in the dorsal root ganglia (DRG) during pain and relief. Total RNA from the DRG revealed a sexually dimorphic expression for injury and relief caused by COX-2 inhibition. Of note, both males and females experience increased expression of activating transcription factor 3 (Atf3), however, only the female DRG shows decreased expression following drug treatment. Alternatively, S100A8 and S100A9 expression appear to play a sex specific role in relief in males. The sex differences in RNA expression reveal that comparable behavior does not necessitate the same gene expression. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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13 pages, 1928 KiB

Open AccessArticle

SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis

by Michishige Terasaki, Keita Shibata, Yusaku Mori, Tomomi Saito, Takanori Matsui, Makoto Ohara, Tomoyasu Fukui, Keiji Hasumi, Yuichiro Higashimoto, Koji Nobe and Sho-ichi Yamagishi

Int. J. Mol. Sci. 2023, 24(7), 6505; https://doi.org/10.3390/ijms24076505 - 30 Mar 2023

Cited by 5 | Viewed by 1971

Abstract

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in [...] Read more.

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs–RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe^−/−) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe^−/− mice ex vivo. Although administration of SMTP-44D to Apoe^−/− mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe^−/− mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe^−/− mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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19 pages, 2663 KiB

Open AccessCommunication

Metformin, Empagliflozin, and Their Combination Modulate Ex-Vivo Macrophage Inflammatory Gene Expression

by Adittya Arefin and Matthew C. Gage

Int. J. Mol. Sci. 2023, 24(5), 4785; https://doi.org/10.3390/ijms24054785 - 1 Mar 2023

Cited by 2 | Viewed by 2995

Abstract

Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs [...] Read more.

Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here, we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow-derived macrophages with single agent challenge, which are modulated when added in combination. In silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors, and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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16 pages, 2110 KiB

Open AccessArticle

MLK3 Regulates Inflammatory Response via Activation of AP-1 Pathway in HEK293 and RAW264.7 Cells

by Anh Thu Ha, Jae Youl Cho and Daewon Kim

Int. J. Mol. Sci. 2022, 23(18), 10874; https://doi.org/10.3390/ijms231810874 - 17 Sep 2022

Cited by 8 | Viewed by 2712

Abstract

Inflammation is a critically important barrier found in innate immunity. However, severe and sustained inflammatory conditions are regarded as causes of many different serious diseases, such as cancer, atherosclerosis, and diabetes. Although numerous studies have addressed how inflammatory responses proceed and what kinds [...] Read more.

Inflammation is a critically important barrier found in innate immunity. However, severe and sustained inflammatory conditions are regarded as causes of many different serious diseases, such as cancer, atherosclerosis, and diabetes. Although numerous studies have addressed how inflammatory responses proceed and what kinds of proteins and cells are involved, the exact mechanism and protein components regulating inflammatory reactions are not fully understood. In this paper, to determine the regulatory role of mixed lineage kinase 3 (MLK3), which functions as mitogen-activated protein kinase kinase kinase (MAP3K) in cancer cells in inflammatory response to macrophages, we employed an overexpression strategy with MLK3 in HEK293 cells and used its inhibitor URMC-099 in lipopolysaccharide (LPS)-treated RAW264.7 cells. It was found that overexpressed MLK3 increased the mRNA expression of inflammatory genes (COX-2, IL-6, and TNF-α) via the activation of AP-1, according to a luciferase assay carried out with AP-1-Luc. Overexpression of MLK3 also induced phosphorylation of MAPKK (MEK1/2, MKK3/6, and MKK4/7), MAPK (ERK, p38, and JNK), and AP-1 subunits (c-Jun, c-Fos, and FRA-1). Phosphorylation of MLK3 was also observed in RAW264.7 cells stimulated by LPS, Pam3CSK, and poly(I:C). Finally, inhibition of MLK3 by URMC-099 reduced the expression of COX-2 and CCL-12, phosphorylation of c-Jun, luciferase activity mediated by AP-1, and phosphorylation of MAPK in LPS-treated RAW264.7 cells. Taken together, our findings strongly suggest that MLK3 plays a central role in controlling AP-1-mediated inflammatory responses in macrophages and that this enzyme can serve as a target molecule for treating AP-1-mediated inflammatory diseases. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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Review

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30 pages, 892 KiB

Open AccessReview

Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases

by Michael Poppell, Grace Hammel and Yi Ren

Int. J. Mol. Sci. 2023, 24(6), 5925; https://doi.org/10.3390/ijms24065925 - 21 Mar 2023

Cited by 11 | Viewed by 5461

Abstract

Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune [...] Read more.

Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases. Full article

(This article belongs to the Special Issue Immune Modulation of Macrophages)

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