Excessive IL-4 environment enhances osteoclastogenesis and modulates inflammatory cell differentiation in bone loss associated with food allergic enteropathy

Abstract

Background: Severe Th2 inflammatory diseases, including food allergy, are known to be associated with osteoporosis. However, while IL-4 inhibits osteoclast differentiation, detailed mechanisms of osteoporosis caused under IL-4-excessive environments remain unclear.

Methods: OVA23-3 mice are transgenic mice expressing OVA-specific T-cell receptors and develop significant IL-4-producing T-cell responses resulting in food-allergic enteropathy associated with osteoporosis when fed an egg white (EW) diet. This enteropathy is characterized by phases of inflammation and desensitization; bone loss develops during the inflammatory phase with the onset of allergic enteropathy and is maintained during the desensitization phase when the enteropathy is alleviated by immunological tolerance induction by continuous EW-feeding. We used this model to elucidate the mechanism of food antigen-induced osteoporosis, particularly in an IL-4-dominant environment.

Results: During the inflammatory phase, EW-feeding promoted osteoclastogenesis with increased mast cells, suppressed by administering anti-IL-4 antibody to the model. This finding suggests a critical role for IL-4 in the induction of osteoclastogenesis, which may be associated with mast cells and eosinophils over-differentiation and lead to osteoporosis. However, during the desensitization phase, the bone loss mechanism switched to high metabolic bone turnover, maintaining osteoclast activity despite amelioration of the enteropathy by continuous EW feeding. The increased number of IL-10-producing Tregs from mesenteric lymph nodes may reduce osteoclastogenesis during the desensitization phase, but did not suppress osteoporosis.

Conclusions: The present study provides a new perspective on a poorly understood mechanism of osteoporosis in severe allergies, suggesting the importance of maintaining bone health in allergic patients, including food allergies.