Hypercytokinemia: Increased or decreased innate immunity?

Abstract

The adipose tissue is an active endocrine organ which secretes proinflammatory cytokines and chemokines resulting into raised serum levels. Hypercytokinemia has been interpreted as raised level of innate immunity and its evolution is interpreted as a response to increased chances of infection under starvation conditions in which the thrifty phenotype evolved. If starvation and infection challenges co-occurred during hunter gatherer life, thrifty genotype and infection resistant genotype may have co-evolved. An inherent weakness of this explanation is that in obesity or insulin resistance there is no evidence of increased resistance to infections. The raised levels of inflammatory cytokines have not been demonstrated to combat infections or enhance wound healing. We suggest that the raised chemokine levels actually decrease peripheral innate immunity. The normal movement of monocyte-macrophages and neutrophils from blood vessels to injured tissue is under a chemokine gradient. A gradient results from the difference between the basal levels of chemokines and those secreted by the injured tissue. Increase in the basal level is expected to weaken the gradient thereby decreasing extravasation and infiltration. Using diffusion kinetics we show that a small rise in basal levels can cause substantial reduction in cell infiltration. This interpretation is consistent with the behavioural switch hypothesis proposed by Watve and Yajnik which suggests that obesity and insulin resistance mark a transition from “soldier” to “diplomat” lifestyle. Hypercytokinemia may have evolved as a mechanism of disinvestment in peripheral innate immunity since the diplomat lifestyle is less injury prone. We evaluate the two alternative hypotheses by available evidence