Adipose Tissue as an Immunological Organ: Adipokines, Low-Grade Inflammation, and Autoimmunity

Adipose tissue (AT), once perceived merely as a simple depot for energy storage, has emerged as a complex immunological organ (1). In human, there are 3 types of AT based on histology and function: brown, beige and white adipose tissue. White adipose tissue (WAT) is the primary site of lipid storage and can be further divided into subcutaneous AT (SAT) and visceral AT (VAT), with VAT associated with the worst metabolic outcomes. Adipose tissues are composed of mature adipocytes, fibroblast-like cells, adipocyte precursors, vascular and immune cells (2).

The adipocyte acts as a central immunomodulatory cell through multiple mechanisms. It produces hormones and cytokines termed as adipokines. Additionally, adipocytes release proinflammatory lipids, secrete chemoattractants to recruit immune cells, manufacture extracellular vesicles (EVs) that act locally and systemically, and can even present antigens to activate or suppress local T cell responses via the MHCII pathway (2).

Immune Cell Composition and Interactions

In a metabolically healthy, lean state, AT harbours an intricate and anti-inflammatory immune landscape. This balance is maintained by regulatory T cells (Tregs), eosinophils, type 2 innate lymphoid cells (ILC2s), and anti-inflammatory M2-like macrophages. These cells produce mediators like IL-10, IL-4, and IL-13, which maintain tissue homeostasis and insulin responsiveness. Adiponectin, a crucial anti-inflammatory adipokine, is highly secreted during this state (3).

In obesity, this balance is disrupted, resulting in a shift toward a chronic, low-grade inflammatory state. There is an increased infiltration and expansion of pro-inflammatory cell types, notably neutrophils, dendritic cells (DCs), T helper type 1 (Th1) cells, Th17 cells, cytotoxic CD8+ T cells, and pro-inflammatory M1-like macrophages. Simultaneously, beneficial cell populations like Tregs and ILC2s decrease (3).

Adapted from Shaikh et al. Nat Rev Endocrinol. 2024 (4)

Adipokines shape Immunity

Unbalanced secretion of adipokines directly fuels dysregulated immune response as shown in several mice model and human studies, suggesting a causal link between obesity and the increased incidence and progression of rheumatic diseases. Here are some examples of increasingly established links:

• Leptin is secreted by adipocytes proportionally to fat mass, leading to high systemic levels in individuals with obesity. Leptin enhances the proliferation and differentiation of CD4+ T cells into Th1 and Th17 cells, activation of macrophages and activates B-cells (5). Increased level of leptin has been associated with higher dsDNA titter in SLE patient and Crohn’s disease severity (6,7).
• In contrast, adiponectin levels are reduced in obesity. Adiponectin promotes anti-inflammatory M2-like macrophage polarization, suppress TNF-induced vascular cell-adhesion molecules expression and decrease type 1 and type 3 immune response in Th cells (8). Lower levels of adiponectin are measured in skin and adipose tissue of psoriasis patients while adiponectin-deficient mice are more sensitive to colitis and dermatitis model (9,10).
• Other classical pro-inflammatory cytokines such as TNFα, IL-6, IFNγ and IL-1 family cytokines, are increasingly produced by both adipocytes and infiltrating immune cells in obesity (11,12).

Evidence from fundamental and translational research is growing that adipose tissue is a key regulator of immune system function. The shift from an anti-inflammatory, homeostatic immune environment in lean adipose tissue toward a chronic, low-grade inflammatory state in obesity not only impair metabolic homeostasis but also affect the course of several autoimmune and rheumatic diseases. These findings raise hopes that targeting these mechanisms could be harnessed to promote favourable outcomes in patients with autoimmune diseases, but a deeper understanding of the adipose–immune system crosstalk will be crucial for developing integrated strategies.

References

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