Cell Type-Specific Immunomodulation Induced by Helminthes: Effect on Metainflammation, Insulin Resistance and Type-2 Diabetes

Abstract

Recent epidemiological studies have documented an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases ("metabolic hygiene hypothesis"). Chronic inflammation leading to insulin resistance (IR) has now been identified as a major etiological factor for a variety of metabolic diseases other than obesity and Type-2 diabetes (metainflammation). One way by which helminth infections such as filariasis can modulate IR is by inducing a chronic, nonspecific, low-grade, immune suppression mediated by modified T-helper 2 (Th2) response (induction of both Th2 and regulatory T cells) which can in turn suppress the proinflammatory responses and promote insulin sensitivity (IS). This article provides evidence on how the cross talk between the innate and adaptive arms of the immune responses can modulate IR/sensitivity. The cross talk between innate (macrophages, dendritic cells, natural killer cells, natural killer T cells, myeloid derived suppressor cells, innate lymphoid cells, basophils, eosinophils, and neutrophils) and adaptive (helper T [CD4⁺] cells, cytotoxic T [CD8⁺] cells and B cells) immune cells forms two opposing circuits, one associated with IR and the other associated with IS under the conditions of metabolic syndrome and helminth-mediated immunomodulation, respectively.

Figure 1.

Innate and adaptive immune cross talk in insulin resistance (IR). Infiltration of classically activated/M1 macrophages into adipose tissue sets in redox stress and inflammation, which leads to IR (1). The Th1, Th17, and CTLs get recruited before macrophage entry and promote macrophage recruitment/polarization. (2) Pathogens such as viruses and bacteria activate dendritic cells (DCs) and promote Th1 and Th17 differentiation. (3) Neutrophils (Nθ), basophils (Bθ), and B cells get recruited into AT and promote inflammation (4).

Figure 2.

Innate and adaptive immune cross talk in insulin sensitivity (IS). IS in the adipose tissue is maintained by the resident M2 macrophages, which are maintained in their “alternatively activated” state by the resident eosinophils (Eθ) (1).The resident innate lymphoid cells 2 (ILC-2) promote eosinophil recruitment and activation (2). During helminth infection, tolerogenic and myeloid dendritic cells (mDCs) get activated (3) which in turn promote Tregs and Th2 differentiation (4).Th2 and Tregs also aid in M2 polarization (5). The role played by invariant natural killer T cells (iNKTs) in IS is not clearly known (6).