The endoplasmic reticulum stress protein GRP94 modulates cathepsin L activity in M2 macrophages in conditions of obesity-associated inflammation and contributes to their pro-inflammatory profile.
Int J Obes (Lond)
; 48(6): 830-840, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38351251
ABSTRACT
BACKGROUND/OBJECTIVES:
Adipose tissue macrophages (ATM) are key actors in the pathophysiology of obesity-related diseases. They have a unique intermediate M2-M1 phenotype which has been linked to endoplasmic reticulum (ER) stress. We previously reported that human M2 macrophages treated with the ER stress inducer thapsigargin switched to a pro-inflammatory phenotype that depended on the stress protein GRP94. In these conditions, GRP94 promoted cathepsin L secretion and was co-secreted with complement C3. As cathepsin L and complement C3 have been reported to play a role in the pathophysiology of obesity, in this work we studied the involvement of GRP94 in the pro-inflammatory phenotype of ATM.METHODS:
GRP94, cathepsin L and C3 expression were analyzed in CD206 + ATM from mice, WT or obesity-resistant transgenic fat-1, fed a high-fat diet (HFD) or a standard diet. GRP94 colocalization with cathepsin L and C3 and its effects were analyzed in human primary macrophages using thapsigargin as a control to induce ER stress and palmitic acid (PA) as a driver of metabolic activation.RESULTS:
In WT, but not in fat-1 mice, fed a HFD, we observed an increase in crown-like structures consisting of CD206 + pSTAT1+ macrophages showing high expression of GRP94 that colocalized with cathepsin L and C3. In vitro experiments showed that PA favored a M2-M1 switch depending on GRP94. This switch was prevented by omega-3 fatty acids. PA-induced GRP94-cathepsin L colocalization and a decrease in cathepsin L enzymatic activity within the cells (while the enzymatic activity in the extracellular medium was increased). These effects were prevented by the GRP94 inhibitor PU-WS13.CONCLUSIONS:
GRP94 is overexpressed in macrophages both in in vivo and in vitro conditions of obesity-associated inflammation and is involved in changing their profile towards a more pro-inflammatory profile. It colocalizes with complement C3 and cathepsin L and modulates cathepsin L activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catepsina L
/
Estresse do Retículo Endoplasmático
/
Inflamação
/
Macrófagos
/
Obesidade
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article