Giants of immunity: uncovering a role for Atf3 in multinucleated giant cell formation
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| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
Köln
2020
|
| Subjects: | |
| Online Access: | Inhaltsverzeichnis Inhaltsverzeichnis |
| Physical Description: | IX, 97 Seiten Illustrationen |
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MARC
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| 245 | 1 | 0 | |a Giants of immunity |b uncovering a role for Atf3 in multinucleated giant cell formation |c vorgelegt von Andreia Cláudia Pereira Correia |
| 264 | 1 | |a Köln |c 2020 | |
| 300 | |a IX, 97 Seiten |b Illustrationen | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |b Dissertation |c Universität zu Köln |d 2020 | ||
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Record in the Search Index
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|---|---|
| adam_text | CONTENT
ABSTRACT
.............................................................................................................................................
I
ZUSAMMENFASSUNG
.......................................................................................................................
ILL
LIST
OF
FIGURES
..................................................................................................................................
V
LIST
OF
TABLES
.................................................................................................................................VII
LIST
OF
ABBREVIATIONS
....................................................................................................................
VIII
1.
INTRODUCTION
.................................................................................................................................
1
1.1.
ONE
FOR
ALL
AND
ALL
FOR
ONE:
MACROPHAGES
LEAD
THE
WAY
...........................................................
1
1.2.
GOING
BIG:
FROM
MACROPHAGES
TO
MULTINUCLEATED
GIANT
CELLS
..................................................
3
1.2.1.
HOMEOSTASIS:
OSTEOCLASTS
....................................................................................................
3
1.2.2.
INFLAMMATORY
CONDITIONS:
MGCS
...........................................................................................4
1.2.2.1.
INERT
GRANULOMAS:
FOREIGN
BODY
REACTION
.........................................................................
5
1.2.2.2.
INFECTIOUS
GRANULOMAS:
TUBERCULOSIS
...............................................................................
6
1.3.
MECHANISMS
OF
MULTINUCLEATION
...........................................................................................
9
1.3.1.
ACYTOKINETIC
CELL
DIVISION
.......................................................................................................
9
1.3.2.
CELL-CELL
FUSION
....................................................................................................................
10
1.3.2.1.
ACQUISITION
OF
FUSION
COMPETENCY
...................................................................................
11
1.3.2.2.
CHEMOTAXIS
......................................................................................................................
12
1.3.2.3.
CELL-CELL
ADHESION
............................................................................................................
13
1.3.2.4. LIPID
REGULATION
DURING
PORE
FORMATION
............................................................................
14
1.3.2.5. ROLE
OF
CELLULAR
CYTOSKELETON
IN
REGULATION
OF
CELL
MIGRATION
AND
FUSION
.......................
15
1.4.
HOW
DO
MACROPHAGES
COPE
WITH
MECHANICAL
STRESS?
..........................................................
18
1.5.
AIMS
.......................................................................................................................................
21
2.
RESULTS
..................................................................................................................................
23
2.1.
THE
FORMATION
OF
MGCS
IN
RESPONSE
TO
IL-4
IS
CHARACTERIZED
BY
MARKED
CHANGES
IN
CELL
MORPHOLOGY
...................................................................................................................................
23
2.2.
ACYTOKINETIC
CELL
DIVISION
AS
WELL
AS
CELL-CELL
FUSION
UNDERLIE
IL-4-INDUCED
MGC
FORMATION
.......................................................................................................................................
24
2.3.
CELL
FUSION
RELIES
ON
CYTOSKELETON
DYNAMICS
.........................................................................
25
2.4.
ATF3,
BUT
NOT
JDP2,
IS
UPREGULATED
IN
IL-4-STIMULATED
MACROPHAGES
..................................
27
2.5.
ATF3
K0
MICE
ARE
HOMOZYGOUS
VIABLE
AND
SHOW
INCREASED
EXPRESSION
OF
INFLAMMATORY
MEDIATORS
..............................
27
2.6.
ATF3
IS
REQUIRED
FOR
IL-4-MEDIATED
MACROPHAGE
FUSION,
BUT
NOT
ACYTOKINETIC
CELL
DIVISION
.........................................................................................................................................
29
2.7.
ATF3
K0
BMDMS
ACTIVATE
EXPRESSION
OF
FUSOGENIC
GENES
DOWNSTREAM
OF
IL-4
SIGNALING
.......................................................................................................................................
32
2.8.
ATF3
REGULATES
ACTIN-DRIVEN
CELL
MEMBRANE
DYNAMICS
.....................................................
36
2.9
ATF3
LOSS
INTERFERES
WITH
ACTIN
CYTOSKELETON
TURNOVER
AND
ARCHITECTURE
.................................
39
2.10.
ATF3
REGULATES
NUCLEAR
LAMINA
MORPHOLOGY
AND
COMPOSITION
............................................42
2.11
ATF3-DEPENDENT
REGULATION
OF
NUCLEAR
LAMINA
IS
ESSENTIAL
FOR
THE
MAINTENANCE
OF
GENOME
INTEGRITY
..........................................................................................................................................45
2.12.
ATF3
LOSS
LEADS
TO
P53
ACTIVATION
.......................................................................................
46
2.13.
ATF3
REGULATES
MULTINUCLEATION
DOWNSTREAM
OF
IL-4
BUT
NOT
TLR2
SIGNALING
.....................48
3.
DISCUSSION
..............................................................................................................................
52
3.1.
IL-4-MEDIATED
MACROPHAGE
CELL
FUSION
DEMANDS
DYNAMIC
CYTOSKELETAL
REARRANGEMENTS..
54
3.2
ATF3
IS
INDISPENSABLE
FOR
PORE
FORMATION
IN
RESPONSE
TO
IL-4-DRIVEN
CELL
FUSION
................
54
3.3
ATF3
MEDIATES
ACTIN
CYTOSKELETON
DYNAMICS
IN
MACROPHAGES,
IN
RESPONSE
TO
IL-4
............
56
3.4
ATF3-MEDIATED
ACTIN
CYTOSKELETAL
DYNAMICS
IS
REQUIRED
FOR
PODOSOME
STABILIZATION
..........
58
3.5
ATF3
MEDIATES
NUCLEAR
MECHANOSENSING
IN
RESPONSE
TO
IL-4
..............................................
59
3.6
ATF3-MEDIATED
MECHANOSENSORY
RESPONSE
IS
ESSENTIAL
TO
MAINTAIN
GENOME
INTEGRITY
.......
61
3.7
ATF3
IS
NOT
A
GENERAL
REGULATOR
OF
MACROPHAGE
MULTINUCLEATION
...........................................
63
3.8
CONCLUSION
AND
FUTURE
PERSPECTIVES
.....................................................................................
64
4.
MATERIALS
AND
METHODS
..........................................................................................................
65
4.1.
GENERATION
OF
ATF3
FULL
BODY
KNOCKOUT MOUSE
LINE
WITH
CRISPR/-CAS9
TECHNIQUE
...........
70
4.2.
MOUSE
LINES
AND
HANDLING
......................................................................................................
71
4.3.
MOUSE
GENOTYPING
.................................................................................................................
71
4.4. BONE
MARROW-DERIVED
MACROPHAGES
(BMDMS)
ISOLATION
AND
CELL
CULTURE
..........................
72
4.5.
IMMUNOFLUORESCENCE
............................................................................................................
72
4.6.
RNA
ISOLATION
AND
QUANTITATIVE
REVERSE
TRANSCRIPTION
PCR
(RT-QPCR)
............................
73
4.7.
IMMUNOBLOTTING
.....................................................................................................................
73
4.8.
DETERMINING
G-
TO
F-ACTIN
RATIO
............................................................................................
74
4.9.
FLOW
CYTOMETRY
......................................................................................................................
74
4.10.
ELECTRON
MICROSCOPY
...........................................................................................................
75
4.11.
IMAGE
ACQUISITION
AND
PROCESSING
.....................................................................................
75
5.
REFERENCES
..............................................................................................................................
77
6.
ERKLARUNG
.................................................................................................................................
98
|
| adam_txt |
CONTENT
ABSTRACT
.
I
ZUSAMMENFASSUNG
.
ILL
LIST
OF
FIGURES
.
V
LIST
OF
TABLES
.VII
LIST
OF
ABBREVIATIONS
.
VIII
1.
INTRODUCTION
.
1
1.1.
ONE
FOR
ALL
AND
ALL
FOR
ONE:
MACROPHAGES
LEAD
THE
WAY
.
1
1.2.
GOING
BIG:
FROM
MACROPHAGES
TO
MULTINUCLEATED
GIANT
CELLS
.
3
1.2.1.
HOMEOSTASIS:
OSTEOCLASTS
.
3
1.2.2.
INFLAMMATORY
CONDITIONS:
MGCS
.4
1.2.2.1.
INERT
GRANULOMAS:
FOREIGN
BODY
REACTION
.
5
1.2.2.2.
INFECTIOUS
GRANULOMAS:
TUBERCULOSIS
.
6
1.3.
MECHANISMS
OF
MULTINUCLEATION
.
9
1.3.1.
ACYTOKINETIC
CELL
DIVISION
.
9
1.3.2.
CELL-CELL
FUSION
.
10
1.3.2.1.
ACQUISITION
OF
FUSION
COMPETENCY
.
11
1.3.2.2.
CHEMOTAXIS
.
12
1.3.2.3.
CELL-CELL
ADHESION
.
13
1.3.2.4. LIPID
REGULATION
DURING
PORE
FORMATION
.
14
1.3.2.5. ROLE
OF
CELLULAR
CYTOSKELETON
IN
REGULATION
OF
CELL
MIGRATION
AND
FUSION
.
15
1.4.
HOW
DO
MACROPHAGES
COPE
WITH
MECHANICAL
STRESS?
.
18
1.5.
AIMS
.
21
2.
RESULTS
.
23
2.1.
THE
FORMATION
OF
MGCS
IN
RESPONSE
TO
IL-4
IS
CHARACTERIZED
BY
MARKED
CHANGES
IN
CELL
MORPHOLOGY
.
23
2.2.
ACYTOKINETIC
CELL
DIVISION
AS
WELL
AS
CELL-CELL
FUSION
UNDERLIE
IL-4-INDUCED
MGC
FORMATION
.
24
2.3.
CELL
FUSION
RELIES
ON
CYTOSKELETON
DYNAMICS
.
25
2.4.
ATF3,
BUT
NOT
JDP2,
IS
UPREGULATED
IN
IL-4-STIMULATED
MACROPHAGES
.
27
2.5.
ATF3
K0
MICE
ARE
HOMOZYGOUS
VIABLE
AND
SHOW
INCREASED
EXPRESSION
OF
INFLAMMATORY
MEDIATORS
.
27
2.6.
ATF3
IS
REQUIRED
FOR
IL-4-MEDIATED
MACROPHAGE
FUSION,
BUT
NOT
ACYTOKINETIC
CELL
DIVISION
.
29
2.7.
ATF3
K0
BMDMS
ACTIVATE
EXPRESSION
OF
FUSOGENIC
GENES
DOWNSTREAM
OF
IL-4
SIGNALING
.
32
2.8.
ATF3
REGULATES
ACTIN-DRIVEN
CELL
MEMBRANE
DYNAMICS
.
36
2.9
ATF3
LOSS
INTERFERES
WITH
ACTIN
CYTOSKELETON
TURNOVER
AND
ARCHITECTURE
.
39
2.10.
ATF3
REGULATES
NUCLEAR
LAMINA
MORPHOLOGY
AND
COMPOSITION
.42
2.11
ATF3-DEPENDENT
REGULATION
OF
NUCLEAR
LAMINA
IS
ESSENTIAL
FOR
THE
MAINTENANCE
OF
GENOME
INTEGRITY
.45
2.12.
ATF3
LOSS
LEADS
TO
P53
ACTIVATION
.
46
2.13.
ATF3
REGULATES
MULTINUCLEATION
DOWNSTREAM
OF
IL-4
BUT
NOT
TLR2
SIGNALING
.48
3.
DISCUSSION
.
52
3.1.
IL-4-MEDIATED
MACROPHAGE
CELL
FUSION
DEMANDS
DYNAMIC
CYTOSKELETAL
REARRANGEMENTS.
54
3.2
ATF3
IS
INDISPENSABLE
FOR
PORE
FORMATION
IN
RESPONSE
TO
IL-4-DRIVEN
CELL
FUSION
.
54
3.3
ATF3
MEDIATES
ACTIN
CYTOSKELETON
DYNAMICS
IN
MACROPHAGES,
IN
RESPONSE
TO
IL-4
.
56
3.4
ATF3-MEDIATED
ACTIN
CYTOSKELETAL
DYNAMICS
IS
REQUIRED
FOR
PODOSOME
STABILIZATION
.
58
3.5
ATF3
MEDIATES
NUCLEAR
MECHANOSENSING
IN
RESPONSE
TO
IL-4
.
59
3.6
ATF3-MEDIATED
MECHANOSENSORY
RESPONSE
IS
ESSENTIAL
TO
MAINTAIN
GENOME
INTEGRITY
.
61
3.7
ATF3
IS
NOT
A
GENERAL
REGULATOR
OF
MACROPHAGE
MULTINUCLEATION
.
63
3.8
CONCLUSION
AND
FUTURE
PERSPECTIVES
.
64
4.
MATERIALS
AND
METHODS
.
65
4.1.
GENERATION
OF
ATF3
FULL
BODY
KNOCKOUT MOUSE
LINE
WITH
CRISPR/-CAS9
TECHNIQUE
.
70
4.2.
MOUSE
LINES
AND
HANDLING
.
71
4.3.
MOUSE
GENOTYPING
.
71
4.4. BONE
MARROW-DERIVED
MACROPHAGES
(BMDMS)
ISOLATION
AND
CELL
CULTURE
.
72
4.5.
IMMUNOFLUORESCENCE
.
72
4.6.
RNA
ISOLATION
AND
QUANTITATIVE
REVERSE
TRANSCRIPTION
PCR
(RT-QPCR)
.
73
4.7.
IMMUNOBLOTTING
.
73
4.8.
DETERMINING
G-
TO
F-ACTIN
RATIO
.
74
4.9.
FLOW
CYTOMETRY
.
74
4.10.
ELECTRON
MICROSCOPY
.
75
4.11.
IMAGE
ACQUISITION
AND
PROCESSING
.
75
5.
REFERENCES
.
77
6.
ERKLARUNG
.
98 |
| any_adam_object | 1 |
| any_adam_object_boolean | 1 |
| author | Correia, Andreia Cláudia Pereira |
| author_GND | (DE-588)1213488001 |
| author_facet | Correia, Andreia Cláudia Pereira |
| author_role | aut |
| author_sort | Correia, Andreia Cláudia Pereira |
| author_variant | a c p c acp acpc |
| building | Verbundindex |
| bvnumber | BV046934149 |
| classification_rvk | YC 2700 |
| ctrlnum | (OCoLC)1220880135 (DE-599)DNB1217344454 |
| discipline | Biologie Medizin |
| discipline_str_mv | Biologie Medizin |
| format | Thesis Book |
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| genre | (DE-588)4113937-9 Hochschulschrift gnd-content |
| genre_facet | Hochschulschrift |
| id | DE-604.BV046934149 |
| illustrated | Illustrated |
| index_date | 2024-07-03T15:35:38Z |
| indexdate | 2024-07-10T08:57:54Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-032343018 |
| oclc_num | 1220880135 |
| open_access_boolean | |
| owner | DE-355 DE-BY-UBR DE-83 |
| owner_facet | DE-355 DE-BY-UBR DE-83 |
| physical | IX, 97 Seiten Illustrationen |
| publishDate | 2020 |
| publishDateSearch | 2020 |
| publishDateSort | 2020 |
| record_format | marc |
| spelling | Correia, Andreia Cláudia Pereira Verfasser (DE-588)1213488001 aut Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation vorgelegt von Andreia Cláudia Pereira Correia Köln 2020 IX, 97 Seiten Illustrationen txt rdacontent n rdamedia nc rdacarrier Dissertation Universität zu Köln 2020 Makrophage (DE-588)4193041-1 gnd rswk-swf Immunreaktion (DE-588)4133841-8 gnd rswk-swf Riesenzelle (DE-588)4304362-8 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Immunreaktion (DE-588)4133841-8 s Makrophage (DE-588)4193041-1 s Riesenzelle (DE-588)4304362-8 s DE-604 B:DE-101 application/pdf https://d-nb.info/1217344454/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032343018&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Correia, Andreia Cláudia Pereira Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation Makrophage (DE-588)4193041-1 gnd Immunreaktion (DE-588)4133841-8 gnd Riesenzelle (DE-588)4304362-8 gnd |
| subject_GND | (DE-588)4193041-1 (DE-588)4133841-8 (DE-588)4304362-8 (DE-588)4113937-9 |
| title | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation |
| title_auth | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation |
| title_exact_search | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation |
| title_exact_search_txtP | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation |
| title_full | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation vorgelegt von Andreia Cláudia Pereira Correia |
| title_fullStr | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation vorgelegt von Andreia Cláudia Pereira Correia |
| title_full_unstemmed | Giants of immunity uncovering a role for Atf3 in multinucleated giant cell formation vorgelegt von Andreia Cláudia Pereira Correia |
| title_short | Giants of immunity |
| title_sort | giants of immunity uncovering a role for atf3 in multinucleated giant cell formation |
| title_sub | uncovering a role for Atf3 in multinucleated giant cell formation |
| topic | Makrophage (DE-588)4193041-1 gnd Immunreaktion (DE-588)4133841-8 gnd Riesenzelle (DE-588)4304362-8 gnd |
| topic_facet | Makrophage Immunreaktion Riesenzelle Hochschulschrift |
| url | https://d-nb.info/1217344454/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032343018&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT correiaandreiaclaudiapereira giantsofimmunityuncoveringaroleforatf3inmultinucleatedgiantcellformation |
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