Dataset Information

Impact of immunoproteasome impairment on microglia cell function

ABSTRACT: The ubiquitin-proteasome system maintains the functional proteome of the cells by the clearance of damaged, misfolded, old and/or unneeded proteins. This is particularly important in the brain where protein accumulation has a hallmark of many neurodegenerative diseases that drives neuroinflammation. Microglia are the resident immune cells of the central nervous system and play a major role in the regulation of brain homeostasis via constitutive expression of standard proteasomes and immunoproteasomes (IP). Nevertheless, the impact of IP function on the innate immunity of CNS is not well described. Here, we analyzed ubiquitylated proteins in IP deficient microglia upon enrichment and under different conditions to identify the proteins preferentially degraded by the IP and to investigate the impact of the accumulation of these proteins on microglia function.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Cell Culture, Microglial Cell

SUBMITTER: Simone Venz

LAB HEAD: Simone Venz

PROVIDER: PXD034900 | Pride | 2023-03-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20200429_OV1_SV_BCH_SV_GC_R1_1.msf	Msf
	20200429_OV1_SV_BCH_SV_GC_R1_1.raw	Raw
	20200429_OV1_SV_BCH_SV_GC_R1_2.msf	Msf
	20200429_OV1_SV_BCH_SV_GC_R1_2.raw	Raw
	20200429_OV1_SV_BCH_SV_GC_R1_3.msf	Msf

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Publications

Immunoproteasomes control activation of innate immune signaling and microglial function.

Çetin Gonca G Studencka-Turski Maja M Venz Simone S Schormann Eileen E Junker Heike H Hammer Elke E Völker Uwe U Ebstein Frédéric F Krüger Elke E

Frontiers in immunology 20221006

Microglia are the resident immune cells of the central nervous system (CNS) and play a major role in the regulation of brain homeostasis. To maintain their cellular protein homeostasis, microglia express standard proteasomes and immunoproteasomes (IP), a proteasome isoform that preserves protein homeostasis also in non-immune cells under challenging conditions. The impact of IP on microglia function in innate immunity of the CNS is however not well described. Here, we establish that IP impairmen ...[more]

PMID: 36275769

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Project description:Microglia are the resident mononuclear phagocytes of the CNS parenchyma and represent an initial line of defense against invading microorganisms. Microglia utilize Toll-like receptors (TLRs) for pathogen recognition and TLR2 specifically senses conserved motifs of gram-positive bacteria including lipoproteins, lipoteichoic acids, and peptidoglycan (PGN) leading to cytokine/chemokine production. Interestingly, primary microglia derived from TLR2 knockout (KO) mice over-expressed numerous IL-12 family members, including IL-12p40, IL-12p70, and IL-27 in response to intact S. aureus, but not the less structurally complex TLR2 ligands Pam3CSK4 or PGN. The ability of intact bacteria to augment IL-12 family member expression was specific for gram-positive organisms, since numerous gram-negative strains were unable to elicit exaggerated responses in TLR2 KO microglia. Inhibition of SYK or IRAK4 signaling did not impact heightened IL-12 family member production in S. aureus-treated TLR2 KO microglia, whereas PI3K, MAPK, and JNK inhibitors were all capable of restoring exaggerated cytokine expression to wild type levels. Additionally, elevated IL-12 production in TLR2 KO microglia was ablated by a TLR9 antagonist, suggesting that TLR9 drives IL-12 family member production following exposure to intact bacteria that remains unchecked in the absence of TLR2 signaling. Collectively, these findings indicate crosstalk between TLR2 and TLR9 pathways to regulate IL-12 family member production by microglia. The summation of TLR signals must be tightly controlled to ensure the timely cessation and/or fine tuning of cytokine signaling to avoid nonspecific bystander damage due to sustained IL-12 release. TLR2 KO mice were backcrossed with C57BL/6 animals for a minimum of eight generations prior to use in these studies. Age- and sex-matched C57BL/6 mice were used as wild type (WT) controls. Primary mixed glial cultures were prepared from the cerebral corticies of neonatal mice (2-4 days of age) and microglia were harvested using a differential shaking technique with a purity of >98%. A USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) clinical isolate recovered from a patient with a fatal brain abscess was used to stimulate the microglia isolates. Bacterial strains were heat-inactivated and used to stimulate microglia at 107 colony forming units (cfu)/well for 6 and 12 hours time points. Three replicates of each mouse type (WT, TLR2 KO) at both time points 6 and 12 hours were used for the microarray experiments. Data was only usable for 2 replicates of the KO-12 hr group.