SOCS3 Regulates Dectin-2-Induced Inflammation in PBMCs of Diabetic Patients

Mohammed J A Haider; Zahraa Albaqsumi; Fahd Al-Mulla; Rasheed Ahmad; Fatema Al-Rashed

doi:10.3390/cells11172670

SOCS3 Regulates Dectin-2-Induced Inflammation in PBMCs of Diabetic Patients

Cells. 2022 Aug 28;11(17):2670. doi: 10.3390/cells11172670.

Authors

Mohammed J A Haider¹, Zahraa Albaqsumi², Fahd Al-Mulla³, Rasheed Ahmad², Fatema Al-Rashed²

Affiliations

¹ Department of Biological Sciences, Faculty of Science, Kuwait University, P.O. Box 5969, Kuwait City 13060, Kuwait.
² Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, Kuwait City 15462, Kuwait.
³ Genetics & Bioinformatics, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, Kuwait City 15462, Kuwait.

Abstract

The C-type lectin receptors (CLRs) Dectin-1 and Dectin-2 are involved in several innate immune responses and are expressed mainly in dendritic cells, monocytes, and macrophages. Dectin-1 activation exacerbates obesity, inflammation, and insulin resistance/type 2 diabetes (T2D). However, the role of Dectin-2 is not clear in T2D. This study aims to evaluate the expression and function of Dectin-2 in peripheral blood mononuclear cells (PBMCs) isolated from diabetic patients and non-diabetic controls. Flow-cytometry and qRT-PCR were performed to evaluate the expression of Dectin-2 in different leukocyte subpopulations isolated from T2D patients (n = 10) and matched non-diabetic controls (n = 11). The functional activity of Dectin-2 was identified in PBMCs. CRP, IL-1β, and TNF-α concentrations were determined by ELISA. siRNA transfection and Western blotting were performed to assess p-Syk and p-NF-kB expression. siRNA transfection was performed to knock down the gene of interest. Our results show that Dectin-2 expression was the highest in monocytes compared with other leukocyte subpopulations. The expression of Dectin-2 was significantly increased in the monocytes of T2D patients compared with non-diabetic controls. Dectin-2 expression positively correlated with markers of glucose homeostasis, including HOMA-IR and HbA1c. The expression of inflammatory markers was elevated in the PBMCs of T2D patients. Interestingly, SOCS3, a negative regulator of inflammation, was expressed significantly lowlier in the PBMCs of T2D patients. Moreover, SOCS3 expression was negatively correlated with Dectin-2 expression level. The further analysis of inflammatory signaling pathways showed a persistent activation of the Dectin-2-Syk-NFkB pathway that was instigated by the diminished expression of SOCS3. Dectin-2 activation failed to induce SOCS3 expression and suppress subsequent inflammatory responses in the PBMCs of diabetic patients. siRNA-mediated knockdown of SOCS3 in PBMCs displayed a similar inflammatory phenotype to diabetic PBMCs when exposed to Dectin-2 ligands. Altogether, our findings suggest that elevated Dectin-2 and its relationship with SOCS3 could be involved in the abnormal immune response observed in T2D patients.

Keywords: Candida albicans; Dectin-2; PBMC; SOCS3; T2D; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers / metabolism
Cytokines / metabolism
Diabetes Mellitus, Type 2* / genetics
Diabetes Mellitus, Type 2* / metabolism
Humans
Inflammation / metabolism
Lectins, C-Type*
Leukocytes, Mononuclear* / metabolism
NF-kappa B / metabolism
RNA, Small Interfering / metabolism
Suppressor of Cytokine Signaling 3 Protein* / metabolism

Substances

Biomarkers
Cytokines
Lectins, C-Type
NF-kappa B
RNA, Small Interfering
SOCS3 protein, human
Suppressor of Cytokine Signaling 3 Protein
dectin-2, mouse

Grants and funding

This work was supported and funded by the Kuwait University Research Grant No. [SL01/21] and by the Kuwait Foundation for the Advancement of Sciences (KFAS) grant No. (RA MoH-2022-002).