Treatment with a Novel Chemokine-Binding Protein or Eosinophil Lineage-Ablation Protects Mice from Experimental Colitis

Abstract

Eosinophils are multifunctional leukocytes implicated in numerous inflammatory diseases. The present study was conducted to clarify the precise role of eosinophils in the development of colitis by using eosinophil-depleted mice and a novel chemokine-binding protein that neutralizes CCL11 action. Colitis was induced by administration of dextran sodium sulfate (DSS) to wild-type and eosinophil-deficient ⌬dblGATA-1 mice. Accumulation of eosinophils in the gut of mice given DSS paralleled worsening of clinical score and weight loss. In response to DSS, ⌬dblGATA-1 mice showed virtual absence of eosinophil recruitment, amelioration of clinical score, weight loss, and tissue destruction, and no lethality. There was a decrease in CXCL1 and CCL3 production and decreased neutrophil influx in the intestine of ⌬dblGATA-1 mice. Transfer of bone marrow cells from wild-type mice reconstituted disease manifestation in DSS-treated ⌬dblGATA-1 mice, and levels of CCL11 were increased after DSS treatment and localized to inflammatory cells. Treatment with the chemokine-binding protein evasin-4 at a dose that prevented the function of CCL11 greatly ameliorated clinical score, weight loss, overall tissue destruction, and death rates. In conclusion, the influx of eosinophils is critical for the induction of colitis by DSS. Treatment with a novel chemokine-binding protein decreased eosinophil influx and greatly ameliorated colitis, suggesting that strategies that interfere with the recruitment of eosinophils may be useful as therapy for colitis.

Evaluation of mucositis induced by irinotecan after microbial colonization in germ-free mice

“…The major function of these cells is to protect the host from infection by combating invading micro-organisms and clearing cellular debris. However, activated neutrophils secrete a battery of bioactive substances, such as proteases and reactive oxygen intermediates, which in excess can lead to intestinal tissue damage (Fournier & Parkos, 2012;Vieira et al, 2009). Previous studies have demonstrated the participation of these inflammatory cells in the development of mucositis (Fijlstra et al, 2011;Leitão et al, 2007;Lima et al, 2005).…”

Skin Wound Healing Is Accelerated and Scarless in the Absence of Commensal Microbiota

“…The extent of neutrophil accumulation in the wound tissue was measured by assaying myeloperoxidase (MPO) activity, as described previously (25,26). Briefly, after euthanasia with an overdose of anesthetic, the wound and surrounding skin area were removed and snap frozen in liquid nitrogen.…”

“…In addition, a blood smear was prepared and stained with Panótico Rápido (a Diff Quick-based stain, Laborclin, Brasil). The percentage of monocytes and neutrophils was determined using standard morphological criteria (25).…”

CCR3 Blockade Attenuates Eosinophilic Ileitis and Associated Remodeling

“…Our previous work highlighted a significant role for major basic protein (MBP) in intestinal epithelial barrier disruption after 7 days of colonic inflammation. 14 Eosinophil-null mice (PHIL and ⌬dblGATA) are relatively protected from DSS colitis, compared with wild-type controls, 8,11 providing strong evidence for the participation of eosinophils in the early stages of intestinal inflammation. Finally, in a study transmitting ileitis via adoptive transfer of CD4 ϩ T cells from Th1-cytokine-driven SAMP1/Yit mice into immunodeficient SCID mice injected therapeutically with antibody to the critical eosinophilopoietin IL-5, Takedatsu et al 15 showed improved ileo-colonic inflammation.…”

“…8,10,11 The strongest evidence supporting a pathogenic role for eosinophils in intestinal remodeling measured acute inflammation in the murine dextran sulfate sodium (DSS) colitis model. Forbes et al 12 demonstrated that eosinophil peroxidase (EPO)-null mice were protected from 8 days of DSS colitis.…”