Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid

Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic β-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1β protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1β secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, upregulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex-vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…DHA reduces the IL-8 release induced by pneumolysin in human neutrophils and PMA-induced ROS production in goat neutrophils (Fickl et al, 2005;Pisani et al, 2009). In macrophages, diverse studies performed under in vivo conditions have demonstrated a beneficial effect of DHA and the role of macrophages in cancer, type-1 diabetes, and diabetic wound healing (Jia et al, 2020;Liang et al, 2020;Davanso et al, 2021). Dietary n-3 fatty acids inhibited M2-like macrophage function and the development and progression of castrateresistant prostate cancer in an immunocompetent mouse model (Liang et al, 2020).…”

“…Another study suggested the use of DHA as adjuvant therapy in the treatment of type-1 diabetes. The authors observed that DHA reduced the macrophage inflammatory state and reversed diabetes-induced changes (Davanso et al, 2021 ). A diet containing DHA and EPA showed anti-inflammatory effects and reduced atherogenesis in Apoe–/– mice (Takashima et al, 2016 ).…”

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

“…The link between high fat diet-induced obesity and chronic low-grade inflammation involves an increased pro-inflammatory state, including M1 macrophage polarization [60]. We review here the effects of different FAs on three principal macrophage functions: chemokine production, phagocytosis and adhesion.…”

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

“…Interestingly, NLRP3 inflammasome played a protective role in early stage of T1D in IRAK-M (−/−) NOD mice (168). In human islets, NLRP3 inflammasome can be activated, and secretion of IL-1b increases by the presence of LPS and ATP (102). As an upstream factor activating IL-1b, NLRP3 inflammasome may have a potential function in T1D.…”