Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity

Abstract

The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.

E4BP4 in macrophages induces an anti-inflammatory phenotype that ameliorates the severity of colitis

“…In the present study, in a largely unbiased approach, we found that E4BP4 regulates Il4ra expression as a potential mechanism by which E4BP4 induces anti-inflammation in macrophages. This is supported by an independent study showing that administration of BMDM stimulated with the Th2 cytokine IL-4 improved the severity of experimental colitis in mice 52 . IL-4R in macrophages is known to form a complex with IL-4 and induce polarization toward alternatively activated macrophages (AAM, also earlier known as M2) 53 .…”

E4BP4 in macrophages induces an anti-inflammatory phenotype that ameliorates the severity of colitis

“…In the present study, in a largely unbiased approach, we found that E4BP4 regulates Il4ra expression as a potential mechanism by which E4BP4 induces anti-inflammation in macrophages. This is supported by an independent study showing that administration of BMDM stimulated with the Th2 cytokine IL-4 improved the severity of experimental colitis in mice 49 . IL-4R in macrophages is known to form a complex with IL-4 and induce polarization toward alternatively-activated macrophages (AAM, also earlier known as M2) 50 .…”

The pharmacological evidence of the chang-yan-ning formula in the treatment of colitis

“…First, excessive inflammatory responses exacerbate the compromised colon epithelium, with consequent mucosal lesions and colonic erosion. By referring to the retrieved hub genes and their influenced pathways, IL-1β, IL-17 ( Yin et al, 2021 ), TNFα ( Xiao et al, 2016 ), and HIF-1α ( Bäcker et al, 2017 ; Kerber et al, 2020 ) are pro-inflammatory in colitis mice, and IL-4 ( Callejas et al, 2021 ), CCL2 ( Maharshak et al, 2010 ), and PPARγ ( Zhao et al, 2018 ) are conducive to remission. The increased IL-1b and TNF serum levels and enhanced HIF-1 and IL-10 expression in colitis mice were suppressed by CYN therapy, and the treatment facilitated IL-4, CCL2, and PPARγ expression.…”