Free immunoglobulin light chain (FLC) promotes murine colitis and colitis-associated colon carcinogenesis by activating the inflammasome

Abstract

Numerous studies have demonstrated that free Ig light chain (FLC), a novel inflammation mediator, participates in many inflammatory diseases by activating mast cells and extending the survival of neutrophils. However, it remains unclear whether FLC is involved in colitis and colitis-associated colon carcinogenesis (CAC). In this study, we found a significant increase in FLC in murine models of DSS (Dextran Sulfate Sodium Salt)-induced colitis and CAC compared to controls. Peptide F991, a functional blocker of FLC, significantly attenuated colitis progression, which included abrogating the development of diarrhea and tumor burden, elevating survival rate, greatly reducing the infiltration of inflammatory cells (such as ROS+ active neutrophils), especially reducing tumorigenesis in CAC. Furthermore, we demonstrated that F991 inhibited the activation of the inflammasome by reducing the expression of cleaved caspase-1 and the maturation of IL-1β and IL-18. Altogether, our findings demonstrate that FLC can promote the pathogenesis of colitis and CAC and may be used as novel biomarker for the diagnosis of inflammatory bowel disease. Additionally, F991 may become a potential therapeutic option for colitis or colorectal cancer.

Immunoglobulin Expression in Cancer Cells and Its Critical Roles in Tumorigenesis

“…In addition, cancer-derived IgG is identified as a functional component of pancreatic cancer cell debris that can induce inflammation by stimulating IL-1β release from tumor-associated macrophages via the TLR4/TRIF/NF-κB pathway ( 50 ). Furthermore, free Ig light chain (FLC) exerts an essential promotive effect on colitis-associated colon carcinogenesis by activating the inflammasome ( 91 ). The FLC blocker F991 can significantly impede the process of colon carcinogenesis by inhibiting the activation of the inflammasome and reducing the levels of cleaved caspase-1, IL-1β and IL-18.…”

Hepatocyte-Derived Igκ Exerts a Protective Effect against ConA-Induced Acute Liver Injury

“…Interestingly, increasing Igκ levels manifested in cytoplasmic filamentous network but remained dotted distribution around the nucleus in ConA-treated hepatocytes. Our previous results showed that FLCs were significantly increased in the colon tissue of dextran sulfate sodium salt (DSS)-induced colitis mice and that F991, an FLC inhibitor, significantly suppressed the progression of DSS-induced colitis [ 23 ]. The above data suggest that Igκ deposition in ConA-treated hepatocytes might be associated with inflammation and liver injury.…”

Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity

“…This came about after realizing that immunoglobulin light chains may help elicit inflammation (38) and occur at increased levels in inflammatory pathologies (39). Anti-FLC peptide F991, a functional inhibitor of the immunoglobulin light chain either in its free form or when in IgE (40), appeared to be able to slow down the progression of colitis, presumably by reducing inflammation (41), but in our own hands, the results were variable. To try to understand both the effect and its complexity/variability, we constructed a detailed differential equation model (42).…”

“…Other than the one we developed and used here, there are no mathematical models that address the (lack of) ability of a peptide drug interfering with IgLC (or IgE) to revert chronic inflammation definitively. This non-robust ability has been the subject of a set of experimental studies by one of the authors of the present paper [ (38,39,65); see also (41)] and served as the inspiration and guidance for both the present and the previous paper (42). The present paper comes with another novelty however; it provides for an explanation of the faltering effects of this type of peptide as well as a number of suggestions on how to improve the robustness of this type of therapy.…”