Leptin Functions in Infectious Diseases

Abstract

Leptin, a pleiotropic protein has long been recognized to play an important role in the regulation of energy homeostasis, metabolism, neuroendocrine function, and other physiological functions through its effects on the central nervous system (CNS) and peripheral tissues. Leptin is secreted by adipose tissue and encoded by the obese (ob) gene. Leptin acts as a central mediator which regulates immunity as well as nutrition. Importantly, leptin can modulate both innate and adaptive immune responses. Leptin deficiency/resistance is associated with dysregulation of cytokine production, increased susceptibility toward infectious diseases, autoimmune disorders, malnutrition and inflammatory responses. Malnutrition induces a state of immunodeficiency and an inclination to death from communicable diseases. Infectious diseases are the disease of poor who invariably suffer from malnutrition that could result from reduced serum leptin levels. Thus, leptin has been placed at the center of many interrelated functions in various pathogenic conditions, such as bacterial, viruses and parasitic infections. We review herein, the recent advances on the role of leptin in malnutrition in pathogenesis of infectious diseases with a particular emphasis on parasitic diseases such as Leishmaniasis, Trypanosomiasis, Amoebiasis, and Malaria.

Keywords: amoebiasis; bacteria; leishmaniasis; leptin; malaria; malnutrition; trypanosomiasis; virus.

Figure 1

The role of leptin in Innate and adaptive immunity: innate immunity; Leptin plays a crucial role in the activation and proliferation of macrophage, neutrophil, and dendritic cells through the up and down regulation of various cytokine/chemokines. Adaptive immunity; Leptin-induced the activation and proliferation of total lymphocytes (T and B cells), regulatory T cells and Naive T cells through the up and down regulation of pro-inflammatory and anti-inflammatory cytokines. The Innate and adaptive immune response induced by leptin signaling through the phosphorylation of MAKP/STAT-3/P13K pathways (–, –55).

Figure 2

The possible model of Leptin and Immune response in malnutrition coupled infectious diseases. In malnutrition, low adipocyte mass causes a reduction of serum leptin level resultant impairment of normal macrophages and lymphocytes activities. Infected macrophages induce the SOCS1 & 3 proteins expression subsequently upregulates ROS scavenging enzyme Thioredoxin which leads to activates SHP1/PTPase molecules. SHP1/PTP1 negatively regulates the JAK/STAT, and MAP-Kinase pathways thus inhibiting IFN–inducible macrophage functions (increased IL-10 and TGF-β level and decreased the IL-12 cytokines in infected macrophage). IL-10 suppresses the NO activity and improves the parasite survival. TGF-β activates SHP1/PTPase activity in lymphocytes through TGF-β receptor (TBR) which leads to lymphocytes apoptosis. In contrast, Leptin treatment inactivated SHP1/PTPase directed pathways and reversed the macrophage activities by up-regulating the pro-inflammatory cytokines (IFNγ, TNF-α, and IL-12) secretion and NO expression. IL-12 cytokine released from activated macrophage upon leptin treatment inhibits the SHP1/PTPase dependent T lymphocytes apoptosis by activation of JAK/STAT pathway. Moreover, Leptin directly inhibits the FasL-dependent T lymphocytes apoptosis by the inhibition of the caspase 8 activity. Caspase-8 then promotes mitochondrial outer membrane permeabilization (MOMP) by diminishing the inhibitory effect of various antiapoptotic and proapoptotic molecules. MOMP results in cytochrome-c release from the mitochondria, enabling activation of a supramolecular complex, the apoptosome that activates caspase-3 to undertake apoptotic cell death (Suppressors of cytokine signaling: SOCS1 & 3; Protein tyrosine phosphatases: SHP1/PTP1, Mitochondrial membrane potential drop: MMP drop, and P: phosphorylation) (–206).