Immunological regulation of metabolism--a novel quintessential role for the immune system in health and disease

Abstract

The hypothalamus-pituitary-thyroid (HPT) axis is an integrated hormone network that is essential for maintaining metabolic homeostasis. It has long been known that thyroid stimulating hormone (TSH), a central component of the HPT axis, can be made by cells of the immune system; however, the role of immune system TSH remains enigmatic and most studies have viewed it as a cytokine used to regulate immune function. Recent studies now indicate that immune system-derived TSH, in particular, a splice variant of TSHβ that is preferentially made by cells of the immune system, is produced by a subset of hematopoietic cells that traffic to the thyroid. On the basis of these and other findings, we propose the novel hypothesis that the immune system is an active participant in the regulation of basal metabolism. We further speculate that this process plays a critical role during acute and chronic infections and that it contributes to a wide range of chronic inflammatory conditions with links to thyroid dysregulation. This hypothesis, which is amenable to empirical analysis, defines a previously unknown role for the immune system in health and disease, and it provides a dynamic connection between immune-endocrine interactions at the organismic level.

Figure 1.

Comparison of human (top lines) and mouse (bottom lines) TSHβ splice-variant nucleotide sequence as reported by our laboratory (16). Green nucleotides are from intron regions that are contiguous with exons 5 and 3 for mouse and human TSHβ, respectively. Red nucleotides are from exons 5 and 3. Black nucleotides differ in mouse compared to human TSHβ.

Figure 2.

Comparison of mouse TSHβ full-length (A) and splice-variant (B) amino acids. Red amino acids are signal peptides; black amino acids are coded for by exon 4; blue amino acids are coded for by exon 5.

Figure 3.

Comparison of mouse (A) and human (B) TSHβ splice-variant amino acid sequence. Red amino acids are the putative signal peptides coded for by the intronal region. Black amino acids are coded for by mouse exon 5 and human exon 3, respectively. The green residues amino acids represent the “seat-belt” region of the TSHβ polypeptide used to dimerize with TSHα.

Figure 4.

Comparison of TSHβ sequences for Homo sapiens (human), Pan troglodytes (chimpanzee), Gorilla gorilla (gorilla), Pongo pygmaus (orangutan), Macaca mulatta (Rhesus monkey), Callithrix jacchus (marmoset), Mus musculus (mouse), Rattis norvigicus (rat), and Bos taurus (bull). Black and green nucleotides designate intron components prior to the beginning of the last exon (red nucleotides; exon truncated) coding for the TSHβ open-reading frame.

Figure 5.

Model of role for leukocyte-derived TSHβ splice variant in the regulation of metabolism. Under normal homeostatic conditions (left panel), thyroid hormone output is regulated by the native form of TSHβ produced by the pituitary. Some splice-variant TSHβ may be produced by the pituitary, though its overall significance may be minimal if produced in low levels. In that situation, the contribution of leukocyte-derived TSH also would be expected to be minimal. Under periods of immunological stress, such as during infection (right panel), leukocytes would contribute heavily to the regulation of thyroid hormone output and metabolic regulation by producing high levels of the TSHβ splice variant that compete for binding of the native form of TSHβ. The net effect would be suppressed levels of circulating thyroid hormones and lower metabolic activity.