Leptin and mucosal immunity

Abstract

Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that leptin deficiency affects both the innate and acquired immune systems. Here, we review recent studies that demonstrate the impact on immunity of a common non-synonomous polymorphism of the leptin receptor. In a Bangladesh cohort of children, the presence of two copies of the ancestral Q223 allele was significantly associated with resistance to amebiasis. Children and mice with at least one copy of the leptin receptor 223R mutation were more susceptible to amebic colitis. Leptin signaling in the intestinal epithelium and downstream STAT3 (signal transducer and activator of transcription 3) and SHP2 (Src homology phosphatase 2) signaling were required for protection in the murine model of amebic colitis. Murine models have also implicated leptin in protection from other infections, including Mycobacterium tuberculosis, Klebsiella pneumoniae, and Streptococcus pneumoniae. Thus, the role of leptin signaling in infectious disease and specifically leptin-mediated protection of the intestinal epithelium will be the focus of this review.

Figure 1. Intestinal Epithelial Cell (IEC) Leptin-mediated Signaling and Protection from Amebiasis

LepRb signaling and hypothesized IEC specific outcomes. Following LepRb mediated activation each signaling molecule is hypothesized to have different effects within IECs. JAK2⇒anti-apoptosis; Tyr985⇒SHP2⇒anti-apoptosis; Tyr985⇒SOCS3⇒signal attenuation; Tyr1077⇒STAT5⇒anti-apoptosis and tight junctions; Tyr1138⇒STAT3⇒hyperproliferation, cytokines and SOCS3. Also depicted are potential leptin-mediated IEC defenses against E. histolytica. These include increased goblet cell number and mucus production, induction of anti-apoptotic pathways, proliferation and differentiation of IECs, secretion of antimicrobial peptides, maintenance of tight junctions, expression of chemokines and cytokines, and alteration of the microbiome.

Figure 2. Leptin Receptor is Expressed in the Intestinal Epithelium During Amebic Colitis

Immunohistochemistry of a colonic biopsy from a patient with acute amebic colitis demonstrates LepR staining (brown) of intestinal epithelium and infiltrating white blood cells and invading E. histolytica trophozoites (red). Figure credit: Kristine M. Peterson, Robert Gilman, and William A. Petri Jr.

Figure 3. Cytokines That Activate STAT3

Schematic of cytokine receptors that activate STAT3. Cytokines included are leptin, IL-6, IL-11, OSM, CT-1, LIF, CLC, CNTF, OSMR, IL-27, IL-12, IL-23, IL-31, IL-10, IL-22, IL-2, IL-7, IL-9, IL-15 and IL-21. JAK-STAT pathway activation results in phosphorylation of STAT3 and translocation of pSTAT3 to the nucleus where it activates the transcription of target genes. Receptors noted by a red star are known to be expressed in IECs, and are predicted to induce cytokine and defensin (antimicrobial peptide) expression, and augment wound-healing.