Microbiota and caspase-1/caspase-8 regulate IL-1β-mediated bone disease

Abstract

A leucine-to-proline missense mutation at residue 98 in the proline-serine-threonine phosphatase interacting protein 2 (Pstpip2) gene leads to autoinflammatory disease that is characterized by splenomegaly, necrosis, and spontaneous development of osteomyelitis in mice (Pstpip2^cmo). Disease progression in these mice resembles that of chronic recurrent multifocal osteomyelitis in humans. Our group and others have shown that disease progression in Pstpip2^cmo mice is mediated by the cytokine IL-1β, independently of inflammasomes or IL-1α. Our recent publication highlighted herein establishes that diet-induced changes in intestinal microbiota provide protection against the development of osteomyelitis in Pstpip2^cmo mice. Moreover, the proteases caspase-1 and caspase-8 have redundant roles in cleaving IL-1β and promoting disease. This addendum reviews the current literature on the Pstpip2^cmo murine disease model and the clinical significance of the role of PSTPIP2 in regulating autoinflammatory osteomyelitis, which is mediated by innate components of immune cells.

Keywords: IL-1beta; Pstpip2; autoinflammatory; caspase; high-fat diet; microbiota; neutrophil; osteomyelitis.

Figure 1.

Schematic representing the crosstalk among genetics, environment (diet), and microbiota that induces bone disease in Pstpip2^cmo mice. IL-1β is a critical cytokine that mediates bone disease in Pstpip2^cmo mice. IL-1β processing is regulated by caspase-1 and caspase-8. Several factors regulate IL-1β in Pstpip2^cmo mice. Pstpip2^cmo mice have a dysregulated gut microbiota that promotes disease pathogenesis. Similarly, diet or environmental factors can influence disease progression in Pstpip2^cmo mice by directly regulating immune cells or the gut microbiota. Thus, the disease pathogenesis in Pstpip2^cmo mice is multifactorial because it requires a close coordination among genetics, diet, and the gut microbiota.

Figure 2.

Caspase-1 and caspase-8 play redundant roles in neutrophils to induce disease in Pstpip2^cmo mice. Here, we propose potential complexes that activate caspase-1 and caspase-8 to promote IL-1β cleavage in neutrophils and promote disease. Pstpip2^cmo mice harbor pathogenic Prevotella, which promotes the upregulation of pro-IL-1β through yet-unknown toll-like receptors. (A) Caspase-1 processes pro-IL-1β in the inflammasome complex containing NLRP3 and ASC. Caspase-8 also functions in redundant complexes to process pro-IL-1β downstream of (B) TNFR1 and (C) Dectin-1.