Can IL-6-receptor blockade rectify burned induced hypermetabolism?

Abdikarim Abdullahi; Mile Stanojcic; Marc Jeschke

Hypermetabolism is a debilitating response after burn injury that has been shown to contribute to multi-organ failure, sepsis, morbidity and mortality. We have previously reported that the cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of burn-induced hypermetabolism. Specifically, the soluble form of the IL-6 receptor (sIL-6R) has been implicated in both adipose tissue browning and persistent inflammation via the acute phase protein serum amyloid a. Tocilizumab, is a clinically approved antibody targeting the IL-6 receptor (IL-6R mAb) that has demonstrated beneficial results in Rheumatoid arthritis patients. Aim: This study was undertaken to examine whether the anti-mouse IL-6R antibody (Tocilizumab analogue) attenuates hypermetabolism and its associated pathology in a preclinical animal burn model.

We hypothesize that blocking IL-6 signaling post-burn injury will attenuate burn-induced hypermetabolism.

Patients with burns admitted to our burn centre and non-burn controls undergoing elective surgeries were consented for blood collection to measure both soluble IL-6 receptor and IL-6. To determine the efficacy of IL-6R blockade in burns, we administered I.P injections of saline control or IL-6R mAb (1.3mg/kg/day) to burned (30% total body surface area) mice daily for 5 days. Subcutaneous white adipose tissue and plasma collected were analyzed for browning markers and metabolic state via histology, gene expression, and lipid profiling. Liver and skin tissue were collected to assess the effects of IL-6R blockade.

Clinically, we show that plasma sIL-6R, but not IL-6, is more sensitive to delineating hypermetabolic burn patients. In a burn mouse model, we also demonstrate that treatment with IL-6R mAb is safe with no adverse effects. In fact, anti-IL-6R mAb treatment in post-burn mice attenuated burn-induced hypermetabolism, characterized by reductions in adipose browning, mitochondrial respiration, and body weight loss. Histopathological analysis also showed reductions in hepatic fat infiltration in post-burn IL-6R mAb treated mice. Importantly, blockade of soluble IL-6R did not impair wound healing in post burn mice, as no differences were present between treated and non-treated groups for collagen deposition and granulation tissue formation in the skin.

Our findings identify sIL-6R as a critical driver of post-burn hypermetabolism, and suggest that selectively blocking this receptor as a novel therapeutic approach to mitigate burn-induced hypermetabolism.