Hsp60 as a Novel Target in IBD Management: A Prospect

Abstract

Inflammatory bowel disease (IBD) encompasses various pathological conditions similar but distinct that share a multifactorial etiology, including involvement of the intestinal barrier function, the immune system, and intestinal microorganisms. Hsp60 is a chaperonin component of the chaperoning system, present in all cells and tissues, including the intestine. It plays important roles in cell physiology outside and inside mitochondria, its canonical place of residence. However, Hsp60 can also be pathogenic in many conditions, the Hsp60 chaperonopathies, possibly including IBD. The various clinico-pathological types of IBD have a complicated mix of causative factors, among which Hsp60 can be considered a putatively important driver of events and could play an etiopathogenic role. This possibility is discussed in this review. We also indicate that Hsp60 can be a biomarker useful in disease diagnosing and monitoring and, if found active in pathogenesis, should become a target for developing new therapies. The latter are particularly needed to alleviate patient suffering and to prevent complications, including colon cancer.

Keywords: Hsp60; chaperoning system; chaperonopathy; chaperonotherapy; immune system; inflammatory bowel disease; intestinal wall; microbiota.

FIGURE 1

Diagram of the natural history of IBD from the standpoint of Hsp60 and its most feared complication, colorectal cancer. (A) Normal colon (or colon of an IBD patient in remission), showing the normal symbiotic flora (top icons; circles of various colors indicate different species of microbes of the normal, healthy microbiota) immersed in the mucous, both forming the functional mucous-microbiota (MuMi) layer, and epithelium with individual cells as rectangles (green) containing few Hsp60 molecules (blue hourglass). Also shown are immune system cells (star), e.g., macrophages and dendritic cells, and a vessel (blood or lymphatic; undulating band with red borders) in the lamina propria. The thick, orange vertical arrow pointing downward indicates initiation or relapse of IBD, illustrated in (B). (B) Inflamed colon of an IBD patient in relapse. The flora is altered (dysbiosis; while circles indicate normal flora, see (A), the incomplete circles of different colors indicate various microbes that are abnormal, not part of the healthy microbiota, and some may be pathogenic by themselves), and epithelial cells are changed (yellow) affected by the pathologic process with elevated levels of Hsp60, which may be involved in the initiation of carcinogenesis by inhibiting the apoptosis of epithelial cells with malignant DNA transformation, as represented by the two epithelial cells in orange (dysplasia; extreme right). Hsp60 is elevated also in immune system cells and is secreted into the extra-cellular space and/or exposed on the surface and stimulates T lymphocytes (black circle with quadrant missing) and secretion of pro-inflammatory cytokines (solid red circles). Secreted Hsp60 can also reach the general circulation as indicated by the hourglasses inside the lumen of the vessel. The thick vertical reddish arrow pointing downward indicates malignant transformation, illustrated in the (C). The green arrow to the right suggests the expected effect (i.e., the reversal to a normal physiological situation) of IBD treatment aiming at inhibiting/blocking the anti-apoptotic and pro-inflammatory effects of Hsp60 (i.e., negative chaperonotherapy, consisting in blocking the pathogenic action of a chaperone). (C) Early (in situ) colon carcinoma developed on an IBD patient. The main feature is the profound transformation of many epithelial cells. Malignant cells are represented by reddish rectangles with altered nuclei, while cells still undergoing transformation (dysplasia) are shown in orange, as those shown in (B), extreme right. Transformed cells have also elevated levels of Hsp60 and secrete the chaperonin into the extracellular space, mostly via exosomes (double-bordered circles). The amount of Hsp60 reaching the general circulation in exosomes or free increases considerably, and can be used as a biomarker for patient follow-up and for monitoring response to treatment. Note in the MuMi layer that the predominance of abnormal microbes (incomplete circles) with regard to the normal microbes (circles) is more marked than in (B).