A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing

Abstract

Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-α in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65-fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-α remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low, indicating that the CIRP-/- mice have already moved into the angiogenesis and tissue formation phase, whereas the WT mice were still in the inflammatory state. These data collectively suggest that a deficiency in CIRP accelerates the wound healing process.

The role of cold‐inducible RNA binding protein in cell stress response

“…Sufferers of other inflammation‐related disorders, such as abdominal aortic aneurysm are also advised to use anti‐CIRP therapies based on animal experiments . Furthermore, CIRP deficiency could also accelerate the inflammation phase and wound healing process . Taken together, these results strongly suggested that extracellular CIRP, as a novel proinflammatory molecule, induces inflammatory responses leading tissue injury (Fig.…”

Nerve regeneration in rat peripheral nerve allografts: Evaluation of cold‐inducible RNA‐binding protein in nerve storage and regeneration

“…Pretreatment of donor nerve allografts with cold preservation decreases immunosuppression requirements and has been used in the clinical setting to reduce nerve allograft rejection (Grand, Myckatyn, Mackinnon, & Hunter, ). Furthermore, CIRP deficiency accelerates the inflammation phase and wound healing process (Idrovo et al, ). All of these reports indicated that reduced immune rejection occurs due to appropriate pretreatment and cryopreservation methods.…”

Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold

“…Today, the quantitative measurement of CIRP levels in peripheral blood using an ELISA kit appears achievable, opening the possibility to investigate CIRP as a new diagnostic marker for sepsis [ 130 ]. Furthermore, CIRP deficiency accelerates inflammation phase and wound healing process [ 131 ]. Overall, extracellular CIRP induces cell damage by inducing inflammatory responses.…”