Toll-Interacting Protein in Resolving and Non-Resolving Inflammation

Abstract

Innate leukocytes manifest dynamic and distinct inflammatory responses upon challenges with rising dosages of pathogen-associated molecular pattern molecules such as lipopolysaccharide (LPS). To differentiate signal strengths, innate leukocytes may utilize distinct intracellular signaling circuitries modulated by adaptor molecules. Toll-interacting protein (Tollip) is one of the critical adaptor molecules potentially playing key roles in modulating the dynamic adaptation of innate leukocytes to varying dosages of external stimulants. While Tollip may serve as a negative regulator of nuclear factor κ of activated B cells signaling pathway in cells challenged with higher dosages of LPS, it acts as a positive regulator for low-grade chronic inflammation in leukocytes programmed by subclinical low-dosages of LPS. This review aims to discuss recent progress in our understanding of complex innate leukocyte dynamics and its relevance in the pathogenesis of resolving versus non-resolving chronic inflammatory diseases.

Keywords: lipopolysaccharide; low-grade inflammation; lysosome fusion; mitochondria; toll-interacting protein; toll-like receptor 4.

Figure 1

Illustration of distinct domains of toll-interacting protein, relevant binding partners, and potential functions.

Figure 2

Potential roles and modulations of toll-interacting protein (Tollip) in acute and chronic inflammation. Under strong and acute inflammatory conditions, cell membrane-localized Tollip serves as a negative inhibitor for nuclear factor κ of activated B cells (NFκB) signaling pathway, facilitates the resolution of inflammation, and clearance of cellular debris as well as excessive lipids. However, under low-grade inflammatory conditions, Tollip undergoes translocation from cellular membrane to mitochondria. Dislocated Tollip loses its homeostatic function, fails to facilitate lysosome fusion. Instead, mitochondrial Tollip may facilitate non-resolving low-grade inflammation.