Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity

Abstract

Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease.

Innate Lymphoid Cell Immunometabolism

“…Although these cells do not display activated phenotypes in lean mice, a subsequent study proposed that group 1 ILCs function to maintain macrophage homeostasis in the visceral white adipose tissue (VAT) by preferentially killing adipose M2 macrophages in vivo [34]. This was suggested to be caused by enhanced expression of the NKG2D ligand RAE-1 on adipose macrophages during homeostasis[34].…”

“…Although these cells do not display activated phenotypes in lean mice, a subsequent study proposed that group 1 ILCs function to maintain macrophage homeostasis in the visceral white adipose tissue (VAT) by preferentially killing adipose M2 macrophages in vivo [34]. This was suggested to be caused by enhanced expression of the NKG2D ligand RAE-1 on adipose macrophages during homeostasis[34]. However, these results are controversial because the consensus in the field is that M2 macrophages serve a protective rather than detrimental role in the homeostasis of the adipose tissue[31, 61], and our laboratory and others, have not observed metabolic defects nor altered M2 macrophage homeostasis in group 1 ILC-deficient mice (T.E.O.…”

“…However, these results collectively suggest that each member of the group 1 ILCs is sufficient to polarize adipose proinflammatory macrophages through HFD-induced IFN-γ production, and therefore represent a functional spectrum of immune cells able to contribute towards insulin resistance during diet-induced obesity. Other recently proposed mechanisms of how group 1 ILCs increase adipose proinflammatory macrophages during HFD, such as increased TNF-α production[32] or decreased killing of adipose M2 macrophages[34] by group 1 ILCs, are likely secondary to enhanced IFN-γ production, because adoptively transferred Ifng −/− group 1 ILCs from HFD fed mice do not increase the density of proinflammatory macrophages in lymphocyte-deficient mice during HFD[13]. Therefore, it is more likely that these alternative mechanisms can contribute to obesity-associated systemic insulin resistance by other mechanisms that will need further investigation.…”

“…liver and adipose tissue) and collectively suggest a broader role for ILCs in the maintenance of both tissue homeostasis and systemic host metabolism[30, 31]. Given the contribution of ILCs to tissue inflammation in other diseases, it may not be surprising that recent studies have also implicated ILCs in the disruption of host tissue homeostasis and systemic metabolism during diet-induced obesity[13, 32–34]. This review summarizes recent findings in the field of ILC biology that address three central questions in the field of immunometabolism: What are the cell-intrinsic metabolic pathways that are utilized by ILCs during activation and homeostasis?…”

Off-label drugs for weight management

“…An immune process appears at a very early stage of adipose accumulation,13 which then induces slowly progressive systemic inflammation. The pragmatic approach, which acknowledges that excess adiposity is most often progressive, is to treat with pharmacotherapy early while the patient is overfat but not yet overweight or obese, whereas the orthodox approach delays treatment withholding pharmacotherapy until adipose-induced inflammatory processes are irreversible.…”