Metabolic Reprogramming and ILC2 Plasticity in Obesity-related Asthma.
Source: PubMed, NCBI / U.S. National Library of Medicine
Obesity-related asthma is a major clinical challenge defined by its unique pathology and resistance to corticosteroids. Here, we reframe this disease through the lens of tissue-specific "maladaptive plasticity" of group 2 innate lymphoid cells (ILC2s). We propose a central dichotomy: in the obese lung, mechanical transduction synergizes with metabolic inflammation to induce a HIF-1α-mediated glycolytic shift in ILC2s. Conversely, in visceral adipose tissue (VAT), chronic metabolic stress drives ILC2 functional exhaustion, suppressing cytokine secretion. This pulmonary glycolytic shift fuels acetyl-CoA accumulation and subsequent epigenetic remodeling, which locks ILC2s into a pathogenic ILC1/ILC3-like phenotype, thereby driving the non-Th2 inflammation characteristic of obesity-related asthma. Furthermore, we describe how systemic metabolic stress propagates through the "adipose-pulmonary" and "gut-pulmonary" axes, which includes neutrophil extracellular traps (NETs) and glucocorticoid receptor isoform imbalances. Collectively, these pathological changes establish a refractory network of corticosteroid resistance, a primary factor contributing to treatment failure in obesity-related asthma. Based on these findings, we propose a novel therapeutic framework termed "Metabolic Resuscitation". This strategy shifts the focus from conventional immunosuppression to restoring cellular homeostasis by targeting key metabolic checkpoints and epigenetic drivers. This review provides
Abstract
Obesity-related asthma is a major clinical challenge defined by its unique pathology and resistance to corticosteroids. Here, we reframe this disease through the lens of tissue-specific "maladaptive plasticity" of group 2 innate lymphoid cells (ILC2s). We propose a central dichotomy: in the obese lung, mechanical transduction synergizes with metabolic inflammation to induce a HIF-1α-mediated glycolytic shift in ILC2s. Conversely, in visceral adipose tissue (VAT), chronic metabolic stress drives ILC2 functional exhaustion, suppressing cytokine secretion. This pulmonary glycolytic shift fuels acetyl-CoA accumulation and subsequent epigenetic remodeling, which locks ILC2s into a pathogenic ILC1/ILC3-like phenotype, thereby driving the non-Th2 inflammation characteristic of obesity-related asthma. Furthermore, we describe how systemic metabolic stress propagates through the "adipose-pulmonary" and "gut-pulmonary" axes, which includes neutrophil extracellular traps (NETs) and glucocorticoid receptor isoform imbalances. Collectively, these pathological changes establish a refractory network of corticosteroid resistance, a primary factor contributing to treatment failure in obesity-related asthma. Based on these findings, we propose a novel therapeutic framework termed "Metabolic Resuscitation". This strategy shifts the focus from conventional immunosuppression to restoring cellular homeostasis by targeting key metabolic checkpoints and epigenetic drivers. This review provides a new mechanistic framework for understanding obesity-related asthma and offers a rationale for developing therapies to reverse treatment resistance.