Showing papers by "Nissi Varki published in 2015"

A red meat-derived glycan promotes inflammation and cancer progression.

Abstract: A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of “red meat” of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.

Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec‐5 and Siglec‐14

Abstract: The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.

Siglec receptors impact mammalian lifespan by modulating oxidative stress

Abstract: Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

The E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1–Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis

Abstract: It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naive T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.

On the apparent rarity of epithelial cancers in captive chimpanzees.

Abstract: Malignant neoplasms arising from epithelial cells are called carcinomas. Such cancers are diagnosed in about one in three humans in ‘developed’ countries, with the most common sites affected being lung, breast, prostate, colon, ovary and pancreas. By contrast, carcinomas are said to be rare in captive chimpanzees, which share more than 99% protein sequence homology with humans (and possibly in other related ‘great apes’—bonobos, gorillas and orangutans). Simple ascertainment bias is an unlikely explanation, as these nonhuman hominids are recipients of excellent veterinary care in research facilities and zoos, and are typically subjected to necropsies when they die. In keeping with this notion, benign tumours and cancers that are less common in humans are well documented in this population. In this brief overview, we discuss other possible explanations for the reported rarity of carcinomas in our closest evolutionary cousins, including inadequacy of numbers surveyed, differences in life expectancy, diet, genetic susceptibility, immune responses or their microbiomes, and other potential environmental factors. We conclude that while relative carcinoma risk is a likely difference between humans and chimpanzees (and possibly other ‘great apes’), a more systematic survey of available data is required for validation of this claim.

Reply to Mackenzie: A comparison of Neu5Gc and α-gal xenoantigens

Abstract: We appreciate the thoughtful comments of K. J. Mackenzie (1) regarding our findings, concerning how a red meat-derived glycan can promote inflammation and cancer progression (2). At first glance, there do indeed appear to be very close similarities between the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) antigen we are describing and the well-known nonhuman “α-Gal” antigen (Galα1-3Galβ1-3/4GlcNAcβ1-R), which is also present in red meat, and can account for allergic reactions to such foods (3). However, there are also significant differences (see table 1 in ref. 4) that make the metabolic details and outcomes of the respective immune responses dissimilar. Although both glycans are foreign antigens that can be processed in the gut and against which humans have circulating antibodies, the released α-gal would become free galactose, which then cannot be reconverted back into α-gal within human cells (because of the human genetic lack of the appropriate α-galactosyltransferase). Therefore, the antibody response against α-gal should remain targeted only against foreign meat glycoconjugates themselves, resulting in a classic allergic reaction. In contrast, the Neu5Gc remains unchanged, can be taken up by human cells, metabolically incorporated by the endogenous biochemical machinery, and presented on human cell surfaces as if biosynthesized in the very same cell (5). Thus, endogenous glycoconjugate-bound Neu5Gc becomes a true xeno-autoantigen, and the xeno-autoantibody response is directed against human cells that have incorporated this molecule (5). Finally, whereas intratumoral injections of α-gal–containing glycolipids have been tried for conversion of human tumors into autologous vaccines (6), we are not aware of any evidence for direct incorporation of diet-derived intact α-gal glycoconjugates into human tumors in vivo. Given these considerations, α-gal antibodies are more likely to be involved in allergic reactions or associated with rejection of xenografts, and probably not related to the chronic inflammation associated with malignancies. However, further studies are needed to be certain, and also to ask if there are other examples of in vivo conversion of dietary xeno-antigens into xeno-autoantigens, besides Neu5Gc.