TYPE Mini Review
PUBLISHED 12 September 2022
DOI 10.3389/fimmu.2022.979414
Role of RGC-32 in multiple
OPEN ACCESS sclerosis and neuroinflammation
EDITED BY
Fumitaka Shimizu,
Yamaguchi University School of
– few answers and
Medicine, Japan
REVIEWED BY
many questions
Shiyou Chen,
University of Missouri, United States
Alexandru Tatomir 1,2, Jacob Cuevas 1, Tudor C. Badea 3,
*CORRESPONDENCE
Horea Rus Dafin F. Muresanu 2, Violeta Rus 4 and Horea Rus 1,5*
1
Department of Neurology, University of Maryland, School of Medicine, Baltimore,
SPECIALTY SECTION MD, United States, 2 Department of Neurosciences, “Iuliu Hatieganu” University of Medicine and
This article was submitted to Pharmacy, Cluj-Napoca, Romania, 3 Research and Development Institute, Faculty of Medicine,
Multiple Sclerosis Transylvania University of Brasov, Brasov, Romania, 4 Department of Medicine, Division of
and Neuroimmunology, Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore,
a section of the journal MD, United States, 5 Neurology Service, Baltimore Veterans Administration Medical Center,
Frontiers in Immunology Baltimore, MD, United States
RECEIVED 27 June 2022
ACCEPTED 22 August 2022
PUBLISHED 12 September 2022
CITATION Recent advances in understanding the pathogenesis of multiple sclerosis (MS)
Tatomir A, Cuevas J, Badea TC, have brought into the spotlight the major role played by reactive astrocytes in
Muresanu DF, Rus V and Rus H (2022)
this condition. Response Gene to Complement (RGC)-32 is a gene induced by
Role of RGC-32 in multiple sclerosis
and neuroinflammation – few answers complement activation, growth factors, and cytokines, notably transforming
and many questions. growth factor b, that is involved in the modulation of processes such as
Front. Immunol. 13:979414.
doi: 10.3389/fimmu.2022.979414 angiogenesis, fibrosis, cell migration, and cell differentiation. Studies have
uncovered the crucial role that RGC-32 plays in promoting the differentiation
COPYRIGHT
© 2022 Tatomir, Cuevas, Badea, of Th17 cells, a subtype of CD4+ T lymphocytes with an important role in MS
Muresanu, Rus and Rus. This is an and its murine model, experimental autoimmune encephalomyelitis. The latest
open-access article distributed under
the terms of the Creative Commons data have also shown that RGC-32 is involved in regulating major
Attribution License (CC BY). The use, transcriptomic changes in astrocytes and in favoring the synthesis and
distribution or reproduction in other
secretion of extracellular matrix components, growth factors, axonal growth
forums is permitted, provided the
original author(s) and the copyright molecules, and pro-astrogliogenic molecules. These results suggest that RGC-
owner(s) are credited and that the 32 plays a major role in driving reactive astrocytosis and the generation of
original publication in this journal is
cited, in accordance with accepted
astrocytes from radial glia precursors. In this review, we summarize recent
academic practice. No use, advances in understanding how RGC-32 regulates the behavior of Th17 cells
distribution or reproduction is and astrocytes in neuroinflammation, providing insight into its role as a
permitted which does not comply with
these terms. potential new biomarker and therapeutic target.
KEYWORDS
RGC-32, multiple sclerosis, EAE (experimental autoimmune encephalomyelitis), radial
glia, neuroinflammation, astrocyte, Th17
Frontiers in Immunology 01 frontiersin.org
, Tatomir et al. 10.3389/fimmu.2022.979414
Introduction of Th17 cells (16) as well as the ability of astrocytes to undergo
reactive changes (17–19).
Recent years have brought an appreciable increase in our In this mini-review, we seek to summarize the most recent
understanding of the pathogenesis of multiple sclerosis (MS), an advances in understanding the contribution of RGC-32 to
autoimmune, demyelinating disorder of the central nervous multiple sclerosis and neuroinflammation, as well as its ability
system (CNS) with a potentially huge socioeconomic impact (1). to regulate astrocyte and Th17 cell biology.
MS pathogenesis results from the combined action of
multiple effectors, including autoreactive myelin-specific T and
B cells, pro-inflammatory cytokines, macrophages, microglia, Th17 cells and their role in MS
astrocytes, and the complement system (2–4). A central role is
played by CD4+ T cells, which are thought to be primed in the Th17 cells differentiate from naïve CD4+ T cells in the
periphery against myelin-specific antigens and then to migrate presence of IL-6 and TGF-b (20). They have high pathogenic
into the CNS, where they launch an inflammatory cascade potential in light of their ability to generate pro-inflammatory
against myelin and oligondedrocytes (OLG), leading to cytokines, including IL-17, IL-21, IL-22 and granulocyte
demyelination and eventually, in the chronic progressive macrophage colony-stimulating factor (GM-CSF) (20, 21). IL-
phases, to axonal loss and neurodegeneration (5). 17 is particularly effective in promoting BBB disruption and in
Astrocytes play vital roles in regulating physiological recruiting immune cells into the CNS (22, 23), while GM-CSF is
processes necessary for maintaining CNS homeostasis, such as highly pro-inflammatory and augments the recruitment of
synaptogenesis, neurotransmitter clearance, ion and water peripheral immune cells into the CNS (23, 24).
balance, formation and maintenance of the blood-brain barrier
(BBB) and regulation of blood flow (6, 7). Astrocytes are also
critical players in the pathogenesis of MS and its murine model, RGC-32 as a key regulator of Th17 cell
experimental autoimmune encephalomyelitis (EAE) by differentiation
sustaining key pathological processes involved in disease
initiation and progression (8–10). Using an RGC-32 knock-out (KO) mouse model, we have
First isolated from rat OLG stimulated by sublytic been able to demonstrate that RGC-32 promotes the
complement activation, RGC-32 was found to be induced by a differentiation of Th17 cells both in vitro and in vivo. When
number of growth factors, hormones, and cytokines, such as compared to wild-type (WT) cells, CD4+ cells isolated from
transforming growth factor (TGF)-b (11–13). RGC-32 RGC-32 KO mice express lower levels of IL-17, as well as some
modulates a number of cellular processes, including cell cycle of the transcription factors necessary for Th17 differentiation,
regulation, cell migration, cellular differentiation, and fibrosis, including retinoic acid receptor-related orphan receptor gamma
and influences pathological processes such as carcinogenesis, t (RORgt), B cell–activating transcription factor (BATF), and
metabolic disorders, atherosclerosis, and autoimmunity (13–15). interferon regulatory factor 4 (IRF4) under Th17-polarizing
Our work has demonstrated that RGC-32 plays an important conditions (16). On the other hand, we have observed that the
role in the pathogenesis of EAE by regulating the differentiation differentiation of Th1, Th2, and Tregs is not affected by the lack
of RGC-32. Further analysis has revealed a defect in SMAD2 and
AKT phosphorylation in RGC-32 KO CD4+ cells, suggesting
that RGC-32 preferentially facilitates the differentiation of Th17
Abbreviations: AGM, axonal guidance molecules; BBB, blood-brain barrier; cells in a TGF-b-dependent and independent manner (16).
CNS, central nervous system; CTGF, connective tissue growth factor; EAE, Moreover, we have observed that RGC-32 KO mice develop
experimental autoimmune encephalomyelitis; ECM, extracellular matrix; a milder EAE phenotype than do their WT counterparts, with a
EPHA7, ephrin receptor type 7A; GM-CSF, granulocyte macrophage lower clinical score at the peak of disease (day 14).
colony-stimulating factor; FBN, fibrillin; FBLN, fibulin; GFAP, glial Immunohistochemical analysis has revealed a smaller
fibrillary acidic protein; HSPG2, heparan sulfate proteoglycan 2; HOPX, inflammatory infiltrate and fewer demyelination foci in the
homeodomain-only protein homeobox; KO, knockout; MMP, matrix spinal cords of RGC-32 KO mice, and a lower number of IL-
metalloproteinase; MS, multiple sclerosis; PLAUR, plasminogen activator, 17+ and GM-CSF+ cells (16).
urokinase receptor; PLXNA1, plexin A1; RGC-32, response gene to Interestingly, one study has shown that overexpression of
complement 32; SPOCK3, Sparc/osteonectin, cwcv and kazal-like domains RGC-32 in peripheral blood mononuclear cells (PBMC) isolated
proteoglycan 3; STAT3, signal transducer and activator of transcription 3; from patients with dilated cardiomyopathy augments the
STC1, stanniocalcin-1; VEGF, vascular endothelial growth factor; VCAN, number of Th17 cells (25). We have also shown that B and T
versican; WDFY1, WD repeat and FYVE domain-containing protein 1; WT, cells from patients with systemic lupus erythematous exhibit
wild type. higher levels of RGC-32 and that overexpression of RGC-32 in
Frontiers in Immunology 02 frontiersin.org
PUBLISHED 12 September 2022
DOI 10.3389/fimmu.2022.979414
Role of RGC-32 in multiple
OPEN ACCESS sclerosis and neuroinflammation
EDITED BY
Fumitaka Shimizu,
Yamaguchi University School of
– few answers and
Medicine, Japan
REVIEWED BY
many questions
Shiyou Chen,
University of Missouri, United States
Alexandru Tatomir 1,2, Jacob Cuevas 1, Tudor C. Badea 3,
*CORRESPONDENCE
Horea Rus Dafin F. Muresanu 2, Violeta Rus 4 and Horea Rus 1,5*
1
Department of Neurology, University of Maryland, School of Medicine, Baltimore,
SPECIALTY SECTION MD, United States, 2 Department of Neurosciences, “Iuliu Hatieganu” University of Medicine and
This article was submitted to Pharmacy, Cluj-Napoca, Romania, 3 Research and Development Institute, Faculty of Medicine,
Multiple Sclerosis Transylvania University of Brasov, Brasov, Romania, 4 Department of Medicine, Division of
and Neuroimmunology, Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore,
a section of the journal MD, United States, 5 Neurology Service, Baltimore Veterans Administration Medical Center,
Frontiers in Immunology Baltimore, MD, United States
RECEIVED 27 June 2022
ACCEPTED 22 August 2022
PUBLISHED 12 September 2022
CITATION Recent advances in understanding the pathogenesis of multiple sclerosis (MS)
Tatomir A, Cuevas J, Badea TC, have brought into the spotlight the major role played by reactive astrocytes in
Muresanu DF, Rus V and Rus H (2022)
this condition. Response Gene to Complement (RGC)-32 is a gene induced by
Role of RGC-32 in multiple sclerosis
and neuroinflammation – few answers complement activation, growth factors, and cytokines, notably transforming
and many questions. growth factor b, that is involved in the modulation of processes such as
Front. Immunol. 13:979414.
doi: 10.3389/fimmu.2022.979414 angiogenesis, fibrosis, cell migration, and cell differentiation. Studies have
uncovered the crucial role that RGC-32 plays in promoting the differentiation
COPYRIGHT
© 2022 Tatomir, Cuevas, Badea, of Th17 cells, a subtype of CD4+ T lymphocytes with an important role in MS
Muresanu, Rus and Rus. This is an and its murine model, experimental autoimmune encephalomyelitis. The latest
open-access article distributed under
the terms of the Creative Commons data have also shown that RGC-32 is involved in regulating major
Attribution License (CC BY). The use, transcriptomic changes in astrocytes and in favoring the synthesis and
distribution or reproduction in other
secretion of extracellular matrix components, growth factors, axonal growth
forums is permitted, provided the
original author(s) and the copyright molecules, and pro-astrogliogenic molecules. These results suggest that RGC-
owner(s) are credited and that the 32 plays a major role in driving reactive astrocytosis and the generation of
original publication in this journal is
cited, in accordance with accepted
astrocytes from radial glia precursors. In this review, we summarize recent
academic practice. No use, advances in understanding how RGC-32 regulates the behavior of Th17 cells
distribution or reproduction is and astrocytes in neuroinflammation, providing insight into its role as a
permitted which does not comply with
these terms. potential new biomarker and therapeutic target.
KEYWORDS
RGC-32, multiple sclerosis, EAE (experimental autoimmune encephalomyelitis), radial
glia, neuroinflammation, astrocyte, Th17
Frontiers in Immunology 01 frontiersin.org
, Tatomir et al. 10.3389/fimmu.2022.979414
Introduction of Th17 cells (16) as well as the ability of astrocytes to undergo
reactive changes (17–19).
Recent years have brought an appreciable increase in our In this mini-review, we seek to summarize the most recent
understanding of the pathogenesis of multiple sclerosis (MS), an advances in understanding the contribution of RGC-32 to
autoimmune, demyelinating disorder of the central nervous multiple sclerosis and neuroinflammation, as well as its ability
system (CNS) with a potentially huge socioeconomic impact (1). to regulate astrocyte and Th17 cell biology.
MS pathogenesis results from the combined action of
multiple effectors, including autoreactive myelin-specific T and
B cells, pro-inflammatory cytokines, macrophages, microglia, Th17 cells and their role in MS
astrocytes, and the complement system (2–4). A central role is
played by CD4+ T cells, which are thought to be primed in the Th17 cells differentiate from naïve CD4+ T cells in the
periphery against myelin-specific antigens and then to migrate presence of IL-6 and TGF-b (20). They have high pathogenic
into the CNS, where they launch an inflammatory cascade potential in light of their ability to generate pro-inflammatory
against myelin and oligondedrocytes (OLG), leading to cytokines, including IL-17, IL-21, IL-22 and granulocyte
demyelination and eventually, in the chronic progressive macrophage colony-stimulating factor (GM-CSF) (20, 21). IL-
phases, to axonal loss and neurodegeneration (5). 17 is particularly effective in promoting BBB disruption and in
Astrocytes play vital roles in regulating physiological recruiting immune cells into the CNS (22, 23), while GM-CSF is
processes necessary for maintaining CNS homeostasis, such as highly pro-inflammatory and augments the recruitment of
synaptogenesis, neurotransmitter clearance, ion and water peripheral immune cells into the CNS (23, 24).
balance, formation and maintenance of the blood-brain barrier
(BBB) and regulation of blood flow (6, 7). Astrocytes are also
critical players in the pathogenesis of MS and its murine model, RGC-32 as a key regulator of Th17 cell
experimental autoimmune encephalomyelitis (EAE) by differentiation
sustaining key pathological processes involved in disease
initiation and progression (8–10). Using an RGC-32 knock-out (KO) mouse model, we have
First isolated from rat OLG stimulated by sublytic been able to demonstrate that RGC-32 promotes the
complement activation, RGC-32 was found to be induced by a differentiation of Th17 cells both in vitro and in vivo. When
number of growth factors, hormones, and cytokines, such as compared to wild-type (WT) cells, CD4+ cells isolated from
transforming growth factor (TGF)-b (11–13). RGC-32 RGC-32 KO mice express lower levels of IL-17, as well as some
modulates a number of cellular processes, including cell cycle of the transcription factors necessary for Th17 differentiation,
regulation, cell migration, cellular differentiation, and fibrosis, including retinoic acid receptor-related orphan receptor gamma
and influences pathological processes such as carcinogenesis, t (RORgt), B cell–activating transcription factor (BATF), and
metabolic disorders, atherosclerosis, and autoimmunity (13–15). interferon regulatory factor 4 (IRF4) under Th17-polarizing
Our work has demonstrated that RGC-32 plays an important conditions (16). On the other hand, we have observed that the
role in the pathogenesis of EAE by regulating the differentiation differentiation of Th1, Th2, and Tregs is not affected by the lack
of RGC-32. Further analysis has revealed a defect in SMAD2 and
AKT phosphorylation in RGC-32 KO CD4+ cells, suggesting
that RGC-32 preferentially facilitates the differentiation of Th17
Abbreviations: AGM, axonal guidance molecules; BBB, blood-brain barrier; cells in a TGF-b-dependent and independent manner (16).
CNS, central nervous system; CTGF, connective tissue growth factor; EAE, Moreover, we have observed that RGC-32 KO mice develop
experimental autoimmune encephalomyelitis; ECM, extracellular matrix; a milder EAE phenotype than do their WT counterparts, with a
EPHA7, ephrin receptor type 7A; GM-CSF, granulocyte macrophage lower clinical score at the peak of disease (day 14).
colony-stimulating factor; FBN, fibrillin; FBLN, fibulin; GFAP, glial Immunohistochemical analysis has revealed a smaller
fibrillary acidic protein; HSPG2, heparan sulfate proteoglycan 2; HOPX, inflammatory infiltrate and fewer demyelination foci in the
homeodomain-only protein homeobox; KO, knockout; MMP, matrix spinal cords of RGC-32 KO mice, and a lower number of IL-
metalloproteinase; MS, multiple sclerosis; PLAUR, plasminogen activator, 17+ and GM-CSF+ cells (16).
urokinase receptor; PLXNA1, plexin A1; RGC-32, response gene to Interestingly, one study has shown that overexpression of
complement 32; SPOCK3, Sparc/osteonectin, cwcv and kazal-like domains RGC-32 in peripheral blood mononuclear cells (PBMC) isolated
proteoglycan 3; STAT3, signal transducer and activator of transcription 3; from patients with dilated cardiomyopathy augments the
STC1, stanniocalcin-1; VEGF, vascular endothelial growth factor; VCAN, number of Th17 cells (25). We have also shown that B and T
versican; WDFY1, WD repeat and FYVE domain-containing protein 1; WT, cells from patients with systemic lupus erythematous exhibit
wild type. higher levels of RGC-32 and that overexpression of RGC-32 in
Frontiers in Immunology 02 frontiersin.org
