Heterogeneity of Group 2 Innate Lymphoid Cells Defines Their Pleiotropic Roles in Cancer, Obesity, and Cardiovascular Diseases

Ikutani, Masashi; Nakae, Susumu

doi:10.3389/fimmu.2022.939378

Cited by 4 publications

(3 citation statements)

References 134 publications

(156 reference statements)

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“…S2J-L). Innate lymphoid cell (ILC)-2 are drivers of Th2 cytokine responses and are protective in obesity ( 31, 48, 49 ). ILC2 were present at small frequencies in the SVF in all groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Ruggiero-Ruff

et al. 2023

Preprint

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Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high fat diet-induced obesity. Compared to male mice, RELMα levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELMα treatment and eosinophil transfer rescued this phenotype. Single cell RNAsequencing of the adipose stromal vascular fraction was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

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Section: Resultsmentioning

confidence: 99%

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Ruggiero-Ruff

et al. 2023

Preprint

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“…In males, WT males SVF fibroblasts increased expression of prostaglandin transporter, Slco2a1 and stromal chemokine Cxcl12 , while KO males upregulated pathways involved in the inhibition of the antioxidative functions, resulting in the accumulation of reactive oxygen species and oxidative stress, such as Txnip . ILC2 are drivers of Th2 cytokine responses and are protective in obesity ( Brestoff et al, 2015 ; Ikutani and Nakae, 2022 ; Lee et al, 2015 ). ILC2 were present at small frequencies in the SVF in all groups ( Figure 5—figure supplement 2M–P ).…”

Section: Resultsmentioning

confidence: 99%

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Ruggiero-Ruff

et al. 2023

eLife

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Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα–macrophage–eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

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“…In fact, preclinical studies have reported protective effects of the expansion of ILC1s in the liver against NAFLD development and its consequences [23]. However, the role of ILC2s still remains imprecise and appears to affect, by either worsening or improving, NAFLD/obesity [24]. Many environmental factors have been studied and most of them appear to be related to ILC2s activation and the production of the profibrotic cytokine IL-13 affecting macrophage selective polarization.…”

Section: Discussionmentioning

confidence: 99%

Chenopodium quinoa’s Ingredients Improve Control of the Hepatic Lipid Disturbances Derived from a High-Fat Diet

Garcia Tejedor,

Haros,

Laparra Llopis

2023

Foods

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This study explored the effects of Chenopodium quinoa’s ingredients on the major lipids’ hepatic profile and the functional selective differentiation of monocyte-derived macrophages and innate lymphoid cells in mice on a high-fat diet. Six-week-old Rag2-/- and Rag2-/-Il2-/- mice received (12 days) a low-molecular-weight protein fraction (LWPF) or the lipid fraction (qLF) obtained from the cold pressing of C. quinoa’s germen. At the end of the experiment, mouse serum and liver tissue were collected. The differences in triglycerides, phospholipids, and the major lipids profile were analyzed. Infiltrated monocyte-derived macrophages and innate lymphoid cells (ILCs) and the expression of liver metabolic stress-related mRNA were measured. In the Rag2-/- mice, feeding them LWPF appeared to improve, to a larger extent, their hepatic capacity to utilize fatty acids in comparison to the qLF by preventing the overwhelming of triglycerides (TGs), despite both reducing the hepatic lipid accumulation. An analysis of the hepatic major lipids profile revealed significant increased variations in the PUFAs and phospholipid composition in the Rag2-/- mice fed with the LWPF or LF. The Rag2-/-Il2-/- mice, lacking innate and adaptive lymphocytes, seemed resistant to mobilizing hepatic TGs and unresponsive to lipid accumulation when fed with the LF. Notably, only the Rag2-/- mice fed with the LWPF showed an increased proportion of hepatic CD68+F4/80+ cells population, with a better controlled expression of the innate immune ‘Toll-like’ receptor (TLR)-4. These changes were associated with an oriented expansion of pluripotential CD117+ cells towards ILC2s (CD117+KLRG1+). Thus, C. quinoa’s ingredients resulted in being advantageous for improving the mechanisms for controlling the hepatic lipotoxicity derived from a high-fat diet, promoting liver macrophage and ILCs expansion to a selective functional differentiation for the control of HFD-driven immune and metabolic disturbances.

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Heterogeneity of Group 2 Innate Lymphoid Cells Defines Their Pleiotropic Roles in Cancer, Obesity, and Cardiovascular Diseases

Cited by 4 publications

References 134 publications

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils

Chenopodium quinoa’s Ingredients Improve Control of the Hepatic Lipid Disturbances Derived from a High-Fat Diet

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