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Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.

Despite the well-accepted view that chronic inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), the function and regulation of eosinophils remain an unclear facet of type II innate immunity in dystrophic muscle. We report the observation that group 2 innate lymphoid cells (ILC2s) are present in skeletal muscle and are the principal regulators of muscle eosinophils during muscular dystrophy. Eosinophils were elevated in DMD patients and dystrophic mice along with interleukin (IL)-5, a major eosinophil survival factor that was predominantly expressed by muscle ILC2s. We also find that IL-33 was upregulated in dystrophic muscle and was predominantly produced by fibrogenic/adipogenic progenitors (FAPs). Exogenous IL-33 and IL-2 complex (IL-2c) expanded muscle ILC2s and eosinophils, decreased the cross-sectional area (CSA) of regenerating myofibers, and increased the expression of genes associated with muscle fibrosis. The deletion of ILC2s in dystrophic mice mitigated muscle eosinophilia and impaired the induction of IL-5 and fibrosis-associated genes. Our findings highlight a FAP/ILC2/eosinophil axis that promotes type II innate immunity, which influences the balance between regenerative and fibrotic responses during muscular dystrophy.

Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB 2 , a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB 2 engagement on VAT ILC2s in a T2DM model. Our results show that CB 2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB 2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB 2 agonist can serve as a candidate for the prevention and treatment of T2DM. [Display omitted] • CB 2 is expressed on adipose-resident ILC2s • CB 2 signaling is mediated via the AKT, ERK1/2, and CREB pathways • CB 2 stimulation of ILC2s protects against and reverses metabolic distress in T2DM • CB 2 induces type 2 cytokine production by human ILC2s, supporting its therapeutic potential CB 2 is highly expressed on adipose-resident ILC2s. Shafiei-Jahani et al. reveal that CB 2 agonists stimulate murine and human ILC2s, enhancing their proliferation and cytokine production through the AKT, ERK1/2, and CREB pathways. This activation promotes an IL-13-dependent mechanism that prevents insulin resistance, enhances glucose tolerance, and reverses established conditions in T2DM. [ABSTRACT FROM AUTHOR]

Here, we examine how prenatal inflammation shapes tissue function and immunity in the lung by reprogramming tissue-resident immune cells from early development. Maternal, but not fetal, type I interferon-mediated inflammation provokes expansion and hyperactivation of group 2 innate lymphoid cells (ILC2s) seeding the developing lung. Hyperactivated ILC2s produce increased IL-5 and IL-13 and are associated with acute Th2 bias, decreased Tregs, and persistent lung eosinophilia into adulthood. ILC2 hyperactivation is recapitulated by adoptive transfer of fetal liver precursors following prenatal inflammation, indicative of developmental programming at the fetal progenitor level. Reprogrammed ILC2 hyperactivation and subsequent lung immune remodeling, including persistent eosinophilia, is concomitant with worsened histopathology and increased airway dysfunction equivalent to papain exposure, indicating increased asthma susceptibility in offspring. Our data elucidate a mechanism by which early-life inflammation results in increased asthma susceptibility in the presence of hyperactivated ILC2s that drive persistent changes to lung immunity during perinatal development. [Display omitted] • Prenatal inflammation induces expanded and hyperactivated lung ILC2s in offspring • Prenatal inflammation programs ILC2 hyperactivation from fetal progenitors • ILC2 hyperactivation is concomitant with remodeling of the lung immune landscape • Hyperactivated ILC2s promote persistent eosinophilia and lung dysfunction in adults López et al. report that prenatal inflammation induces lung ILC2 expansion and hyperactivation programmed from a fetal hematopoietic progenitor. Increased IL-5 and IL-13 production from hyperactivated ILC2s was associated with remodeled lung immunity, including sustained eosinophilia that promoted lung dysfunction and histopathology in adulthood. [ABSTRACT FROM AUTHOR]

Summary: Despite the well-accepted view that chronic inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), the function and regulation of eosinophils remain an unclear facet of type II innate immunity in dystrophic muscle. We report the observation that group 2 innate lymphoid cells (ILC2s) are present in skeletal muscle and are the principal regulators of muscle eosinophils during muscular dystrophy. Eosinophils were elevated in DMD patients and dystrophic mice along with interleukin (IL)-5, a major eosinophil survival factor that was predominantly expressed by muscle ILC2s. We also find that IL-33 was upregulated in dystrophic muscle and was predominantly produced by fibrogenic/adipogenic progenitors (FAPs). Exogenous IL-33 and IL-2 complex (IL-2c) expanded muscle ILC2s and eosinophils, decreased the cross-sectional area (CSA) of regenerating myofibers, and increased the expression of genes associated with muscle fibrosis. The deletion of ILC2s in dystrophic mice mitigated muscle eosinophilia and impaired the induction of IL-5 and fibrosis-associated genes. Our findings highlight a FAP/ILC2/eosinophil axis that promotes type II innate immunity, which influences the balance between regenerative and fibrotic responses during muscular dystrophy.

Adipose tissue homeostasis relies on the interplay between several regulatory lineages, such as type 2 innate lymphoid cells (ILC2s), T helper 2 (Th2) cells, regulatory T cells, eosinophils, and type 2 macrophages. Among them, ILC2s are numerically the dominant source of type 2 cytokines and are considered as major regulators of adiposity. Despite the overlap in immune effector molecules and sensitivity to alarmins (thymic stromal lymphopoietin and interleukin-33) between ILC2s and resident memory Th2 lymphocytes, the role of the adaptive axis of type 2 immunity remains unclear. We show that mice deficient in CD27, a member of the tumor necrosis factor receptor superfamily, are more resistant to obesity and associated disorders. A comparative analysis of the CD4 compartment of both strains revealed higher numbers of fat-resident memory Th2 cells in the adipose tissue of CD27 knockout mice, which correlated with decreased programmed cell death protein 1-induced apoptosis. Our data point to a non-redundant role for Th2 lymphocytes in obesogenic conditions. [Display omitted] • CD27 upregulates PD-1 expression on fat-resident Th2 cells in an intrinsic manner • PD-1 shifts the fate of Th2 toward activation-induced cell death • CD27 deletion results in increased adaptive type 2 immunity in the adipose tissue • The adaptive axis of type 2 immunity protects against obesity and associated disorders The function of Th2 is impaired during obesity. Here, Englebert et al. show that CD27-deficient mice are resistant to obesity and metabolic disorders. This protection correlates with increased Th2 numbers and cytokine production, which sustain visceral eosinophils and RELMα+ macrophages. The data point to a role of PD-1 in this process. [ABSTRACT FROM AUTHOR]

Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma. [Display omitted] • BHB attenuates ILC2-mediated type 2 allergic airway inflammation • BHB indirectly suppresses ILC2s by inhibiting mast-cell-derived IL-2 • Inhibition of IL-2 limits ILC2 proliferation and CD25 expression but not function • BHB inhibits IL-2 production by mast cells in part through GPR109A activation Thio et al. demonstrate the suppressive role of BHB in ILC2-driven type 2 airway inflammation through inhibition of IL-2 production by mast cells. Mechanistically, BHB limits mast cell function through activation of GPR109A signaling. This study underscores the therapeutic potential of ketone body supplementation for the management of allergic asthma. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHAlow) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHAlow tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth. • ILC2s are involved in eosinophil-associated antitumor responses in melanoma • Lactic acid inhibits function and decreases survival of ILC2s • Tumors with decreased lactic acid production exhibit increased infiltration of ILC2s Wagner et al. demonstrate, using melanoma as a model, that group 2 innate lymphoid cells (ILC2s) activated by IL-33 potentiate the eosinophil-associated antitumor response. In contrast, lactate production by melanoma cells impairs function and survival of ILC2s, leading to an enhanced tumor growth. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma. • Murine activated lung ILC2s lack TNFR1 but selectively express TNFR2 • TNF-α enhances ILC2 survival, activation, and induction of AHR using NIK signaling • Inhibition of NIK blocks the costimulatory effects of the TNF/TNFR2 axis in ILC2s • Human ILC2s express TNFR2, and a NIK inhibitor reduces AHR in humanized ILC2 mice TNF-α is highly expressed in the lungs of asthmatic patients. Hurrell et al. show that murine and human ILC2s respond to TNF-α by selectively expressing TNFR2. TNF-α enhances ILC2 survival and cytokine production utilizing the non-canonical NF-κB pathway, leading to increased development of ILC2-dependent AHR. [ABSTRACT FROM AUTHOR]

Complex interactions between immune cells are an important component in the induction of obesity. Here, we show that Il2rg − / − Rag2 − / − mice lacking all lymphocytes are resistant to diet-induced obesity. Transplantation of bone marrow cells from Rag2 − / − mice, which lack only acquired immune cells, into Il2rg − / − Rag2 − / − mice abolishes this resistance, indicating a role for innate lymphoid cells (ILCs) in this process. Mice lacking ILC2 or ILC3 cells, but not natural killer cells, are resistant to obesity. Adoptive transfer of naive ILC2s isolated from the small intestine (SI), but not ILC2s from white adipose tissue (WAT), restores the induction of diet-induced obesity in Il2rg − / − Rag2 − / − mice. Analysis of transcriptional differences reveals that SI-ILC2s express higher levels of IL-2 than do WAT-ILC2s and that blockade of IL-2 signaling impairs weight gain and reduces the populations of ILC2s and ILC3s in the SI, suggesting a role for the IL-2/ILC2/3 axis in the induction of obesity. • Innate lymphoid cells are involved in the induction of diet-induced obesity • ILC2s and ILC3s but not ILC1/NK/exILC3 cells are involved in the induction of obesity • SI-ILC2s but not WAT-ILC2s are involved in the induction of obesity • IL-2 is critical for the maintenance and function of SI-ILC2s and ILC3s Innate lymphoid cells (ILCs) are recently identified lymphocyte populations characterized by the lack of antigen-specific receptors. Sasaki et al. demonstrate the involvement of ILCs in the induction of diet-induced obesity. Specifically, they show that small intestinal ILC2s, but not white adipose tissue ILC2s, are involved in the induction of obesity. [ABSTRACT FROM AUTHOR]

Summary Recent observations clearly highlight the critical role of type 2 innate lymphoid cells in maintaining the homeostasis of adipose tissues in humans and mice. This cell population promotes beiging and limits adiposity directly and indirectly by sustaining a Th2-prone environment enriched in eosinophils and alternatively activated macrophages. Accordingly, the number and function of type 2 innate lymphoid cells (ILC2s) are strongly impaired in obese individuals. In this work, we identify the PD-1-PD-L1 pathway as a factor leading to ILC2 destabilization upon high-fat feeding resulting in impaired tissue metabolism. Tumor necrosis factor (TNF) appears to play a central role, triggering interleukin-33 (IL-33)-dependent PD-1 expression on ILC2s and recruiting and activating PD-L1hi M1 macrophages. PD-1 blockade partially restores the type 2 innate axis, raising the possibility of restoring tissue homeostasis. Graphical Abstract Highlights • PD-1 is upregulated on ILC2s in adipose tissue of obese mice • PD-1 expression is increased in a TNF- and IL-33-dependent manner • PD-1 correlates with impaired ILC2 function in the presence of PD-L1+ macrophages • PD-1 blockade ameliorates glucose tolerance and adaptation to environmental cold The function of ILC2s is compromised during obesity. Here, Oldenhove et al. show that ILC2 inhibition is mediated by the PD-1-PD-L1 pathway. PD-1 blockade in obese mice improved ILC2 function, reinforced type 2 innate responses, and promoted tissue homeostasis. PD-1 may therefore represent a target for immune intervention in obesity-associated disorders. [ABSTRACT FROM AUTHOR]