Local cryotherapy improves adjuvant-induced arthritis through down-regulation of IL-6 / IL-17 pathway but independently of TNFα

Abstract

ObjectivesLocal cryotherapy is widely and empirically used in the adjuvant setting in rheumatoid arthritis treatment, however its own therapeutic and anti-inflammatory effects are poorly characterized. We aimed to evaluate the effects of local cryotherapy on local and systemic inflammation in Adjuvant-induced arthritis, a murine model of rheumatoid arthritis.MethodsThe effects of mild hypothermia (30°C for 2 hours) on cytokine protein levels (Multiplex/ELISA) were evaluated in vitro in cultured rat adjuvant-induced arthritis patellae. In vivo, local cryotherapy was applied twice a day for 14 days in arthritic rats (ice: n = 10, cold gas: n = 9, non-treated: n = 10). At day 24 after the induction of arthritis, cytokine expression levels were measured in grinded hind paws (Q-RT-PCR) and in the plasma (Multiplex/ELISA).ResultsIn vitro, punctual mild hypothermia down-regulated IL-6 protein expression. In vivo, ice showed a better efficacy profile on the arthritis score and joint swelling and was better tolerated, while cold gas induced a biphasic response profile with initial, transient arthritis worsening. Local cryotherapy also exerted local and systemic anti-inflammatory effects, both at the gene and the protein levels: IL-6, IL-17A and IL-1β gene expression levels were significantly down-regulated in hind paws. Both techniques decreased plasma IL-17A while ice decreased plasma IL-6 protein levels. By contrast, we observed no effect on local/systemic TNF-α pathway.ConclusionsWe demonstrated for the first time that sub-chronically applied local cryotherapy (ice and cold gas) is an effective and well-tolerated treatment in adjuvant-induced arthritis. Furthermore, we provided novel insights into the cytokine pathways involved in Local cryotherapy’s local and systemic anti-inflammatory effects, which were mainly IL-6/IL-17A-driven and TNF-α independent in this model.

Effects of whole body cryotherapy in patients with rheumatoid arthritis considering immune parameters

“…These observations were partly confirmed by Guillot et al [22] in rats with adjuvant-induced arthritis exposed to local cryotherapy. These authors showed that the treatment with ice was better tolerated and had beneficial effects on arthritis score and joint swelling, while cold gas application induced transient arthritis worsening.…”

Clinical-like cryotherapy in acute arthritis of the knee improves inflammation signs, pain, joint swelling and motor performance in mice

“…Our study provides a new scientific contribution on the benefits of clinical-like cryotherapy in the treatment of acute knee arthritis in an animal model. It is also used empirically as a complementary treatment for rheumatoid arthritis, with a good tolerance profile when compared to corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs); however, the protocols have not been standardized (7).…”

“…Studying the possible effects of cryotherapy in an arthritis model may be useful for clinical practice. The ice pack was considered a welltolerated modality of therapy (7), and it was effective to ameliorate joint and muscle damage in chronic models of transection of the anterior cruciate ligament (8).…”

Targeted temperature management: State of the Art

“…Therapeutic hypothermia shows normalizing effect on metabolic processes disturbed in ischaemic conditions, including improving metabolism and maintaining glucose balance in the brain, lowering the concentration of lactates formed as a result of anaerobic metabolism, reducing the intensity of cellular acidosis, limiting the secretion of free radicals in damaged neurons, lowering the production of pro-inflammatory cytokines (TNF-α, IL-6), stabilizes the blood-brain barrier and reduces endothelial dysfunction preventing ischaemic damage to tissues and organs [14][15][16][17][18].…”