Leptin in immuno-rheumatological diseases

Abstract

Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders.

Figure 1

Leptin functions in humans. Leptin, mainly secreted by white adipose tissue, travels through the blood, crossing the hematoencephalic barrier. Leptin binds the OB-Rb isoform on neurons in the hypothalamus, activating CART interneurons and inhibiting NPY- and AgRP-interneurons to regulate appetite and energy expenditure. Furthermore, the adipokine modulates sympathetic tone and activity of the hypothalamus–hypophisis–thyroid axis and hypothalamus–hypophisis–adrenal gland axis. Leptin action on the cardiovascular system is complex. Leptin promotes endothelial dysfunction (by immune cell recruitment and interference with endothelium-mediated vasodilatation), plaque formation (by oxidative stress promotion and foam cell formation), plaque destabilization and consequent thrombosis (metalloproteases production and abnormal vascular repair). Leptin exerts a pivotal role in modulating energy expenditure. The adipokine acts on smooth muscles, pancreas and liver by increasing glucose and free fatty acid uptake and promoting fatty acid β-oxidation. In hepatocytes, leptin inhibits lipogenesis and modulates gluconeogenesis. Thereby, leptin is involved in the control of the insulin-resistance/insulin-sensitivity imbalance. Leptin regulation of food intake also exerts its actions on the gastrointestinal tract. AgRP, agouti-related protein; CART, cocaine- and amphetamine-regulated transcript peptide; NPY, neuropeptide-Y.

Figure 2

Leptin signal transduction. The long receptor isoform of leptin is connected to the JAK-STAT intracellular signaling system. As a consequence of letpin binding to the leptin receptor, the following steps occur: (i) JAK2 is activated with a consequent autophosphorylation and phosphorylation of the tyrosine residues on the intracellular domains of the receptor. STAT1, STAT2 and STAT5 bind tyrosine residues. STAT3 proteins form dimers and translocate to the nucleus and modulate c-fos, c-jun, erg1, SOCS3 and AP1 gene expression; (ii) Src homology domains of receptor (SHP2) activates MAPK pathways, including p38, p42/44 and ERK1/2. These pathways control cytokine and chemokine genes; and (iii) leptin activates PLC, leading to PKC activation, followed by JNK stimulation. → refers to activation; ⊣ refers to inhibition. Bcl, B-cell lymphoma; ERK, extracellular signal-regulated kinase; JAK, c-Jun N-terminal kinase-associated kinase; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor-kappa B; ObR, Ob receptor; PKC, protein kinase C; PLC, phospholipase C; SOCS3, suppressor of cytokine signaling-3; STAT, signal transducer and activator of transcription.

Figure 3

Leptin and the immune system. Leptin affects both innate and adaptive immunity. Moreover, leptin promotes immune cell development through sequential steps of myelopoiesis and lymphopoiesis. In innate immunity, leptin modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Leptin promotes monocyte/macrophage activation by inducing CD69, CD25, CD38, CD71 and adhesion molecules expression. Moreover, leptin induces the production of chemokines and proinflammatory cytokines, such as TNF-α, IL-1 and IL-6. Macrophages stimulated by leptin release NO and LTB₄. The adipokine promotes the maturation, activation and cytotoxic capacity of NK cells. In adaptative immunity, leptin affects the generation, maturation and survival of thymic T cells by reducing their rate of apoptosis. In particular, leptin promotes the lymphocyte phenotype switch to CD4⁺CD45RA⁺. Moreover, leptin induces IL-2 and INF-γ production. Recent data suggest the involvement of leptin in the quantitative and qualitative inhibition of naturally occurring T regulatory cells. → refers to activation; ⊣ refers to inhibition. CD, cluster of differentiation; IFN, interferon; Ig, immunoglobulins; IL, interleukin; LT, leukotriene; NK, natural killer; NOS, nitric oxide synthase; ROS, reactive oxygen species; Th, T helper; TNF, tumor necrosis factor.

Figure 4

Leptin and bone homeostasis. Leptin acts as a regulator of bone and cartilage homeostasis. Leptin acts on osteoblasts via two pathways: an indirect pathway and a direct pathway. The first pathway involves sympathetic nervous system activation. In the second pathway, leptin acts directly on osteoblasts. The combination of these actions promotes cortical bone synthesis and trabecular bone loss. Moreover, leptin induces apoptosis and phenotype loss of condrocytes. → refers to activation; ⊣ refers to inhibition. CART, cocaine- and amphetamine-regulated transcript peptide.