Inflammation‐induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic disease with gastrointestinal dysfunction as well as comorbidities such as inflammation-induced bone loss and impaired immune response. Current treatments for IBD all have negative, potentially severe side effects. We aimed to test whether exogenous treatment with irisin, a novel immunomodulatory adipomyokine, could ameliorate IBD-induced lymphatic and bone alterations. Irisin treatment improved both gut and bone outcomes by mitigating inflammation and restoring structure. In the gut, IBD caused colonic lymphatic hyperproliferation into the mucosal and submucosal compartments. This proliferation in the rodent model is akin to what is observed in IBD patient case studies. In bone, IBD increased osteoclast surface and decreased bone formation. Both gut and osteocytes in bone exhibited elevated levels of TNF-α and receptor activator of NF-κB ligand (RANKL) protein expression. Exogenous irisin treatment restored normal colonic lymphatic architecture and increased bone formation rate concurrent with decreased osteoclast surfaces. After irisin treatment, gut and osteocyte TNF-α and RANKL protein expression levels were no different from vehicle controls. Our data indicate that the systemic immunologic changes that occur in IBD are initiated by damage in the gut and likely linked through the lymphatic system. Additionally, irisin is a potential novel intervention mitigating both local inflammatory changes in the gut and distant changes in bone.-Narayanan, S. A., Metzger, C. E., Bloomfield, S. A., Zawieja, D. C. Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease.

Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment

“…Pro-inflammatory cytokines TNF-α and IL-17 are both potent stimulators of osteoclasts and synergize with RANKL to increase osteoclastogenesis 22,24,56,57 . Previously, we identified increased osteocyte pro-inflammatory cytokines in age-matched ambulatory rats with systemic inflammation 51,52 . In this study, we aimed to determine if these factors were altered in HU.…”

“…We, therefore, do not know the time course of changes in osteocyte proteins over the period of disuse nor the impact of irisin treatment at various timepoints. Additionally, we only utilized one dose of irisin that we previously determined mitigated inflammatory responses in chronic models of IBD model 51,52 . We also did not incorporate ambulatory irisin only controls, but based on our previous work (utilizing animals of the same age, sex, strain, and diet), we did not find significant differences in irisin treatment in the ambulatory controls 51,52 .…”

“…One myokine is irisin, originally described as a metabolic regulator stimulating the browning of adipose 45 . Recent research has explored how irisin also increases osteoblasts and cortical bone mass [46][47][48] and regulates inflammation [49][50][51][52][53] . Previously, we discovered that exogenous irisin treatment ameliorated the inflammatory response of gut and bone in a rodent model of chronic IBD 51,52 .…”

“…Recent research has explored how irisin also increases osteoblasts and cortical bone mass [46][47][48] and regulates inflammation [49][50][51][52][53] . Previously, we discovered that exogenous irisin treatment ameliorated the inflammatory response of gut and bone in a rodent model of chronic IBD 51,52 . Another study found that administration of irisin prevented disuse-induced bone loss in HU 54 , but whether this was due to alterations of inflammatory factors has not been previously addressed.…”

Neurodegenerative disease treatments by direct TNF reduction, SB623 cells, maraviroc and irisin and MCC950, from an inflammatory perspective – a Commentary

“…However, the key to both of these texts could well lie in TNF. Albeit discovered for its role in changing white fat to brown [95], irisin had, in systemic inflammatory diseases [96][97][98] and acquired cerebral injury [99], and well before references 23 or 93 appeared, become appreciated to strongly inhibit TNF and functionally related cytokines.…”