Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes

Abstract

Granulocyte macrophage-colony stimulating factor (GM-CSF) is one of the most widely used growth factors for enhancing immune responses and is known to recruit and activate antigen-presenting cells (APCs). This study hypothesized that overexpression of this cytokine within the pancreatic beta-cells would recruit, expand, and activate APCs. The question was whether this would lead to tolerance or autoimmunity to pancreatic antigens. This possibility was tested by preparing transgenic mice (ins-GM-CSF) whose islets expressed murine GM-CSF. By 6-8 weeks of age, these mice developed a profound mononuclear cell infiltration that often overwhelmed the exocrine pancreas, although no changes in enzyme or hormone function were apparent. The majority of the mononuclear infiltrate within the pancreas was identified as F4/80+ macrophages. Transgenic ins-GM-CSF mice had splenomegaly due to a massive increase in the macrophage population. Additionally, mononuclear cells were found within the livers of transgenic mice, with F4/80+ cells also identified within the infiltrate, indicating that GM-CSF-activated mononuclear cells circulated to organs other than the pancreas. To assess the disease potential, this study tested whether macrophage recruitment to the pancreas might accelerate or protect the islets from diabetes. It was found that the induction of diabetes by low-dose streptozotocin (STZ) was delayed and reduced within ins-GM-CSF transgenic mice, in comparison with negative littermates. Together, these data highlight the role of GM-CSF in recruiting APCs such as macrophages. Advanced cellular infiltration does not overtly harm, and may even protect, pancreatic function, as seen with the delay in chemically induced diabetes.

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

“…Our results demonstrate that GM-CSF expressed within the g -cells of the islets of Langerhans enhanced disease incidence in male NOD mice due to an increase in the availability of islet antigen. Recent studies have shown diverse functions of GM-CSF in the immune system [20,21,27,[32][33][34]. Our results suggest that in ins-GM-CSF mice, this height-ened response is mediated by increased numbers of APC infiltrating the pancreas as well as enhanced expression of B7-1 in CD11b + cells.…”

“…To prepare ins-GM-CSF×NOD mice, the approximately 425-bp mouse GM-CSF cDNA was isolated and cloned into a vector containing the human insulin promoter and hepatitis B 3'-untranslated sequence as previously described [21].…”

“…In this latter model, the first stage of disease is associated with proliferation and activation of APC, which leads to migration of pathogenic CD4 + T cells into the gastric mucosa [20]. Recent work by our laboratory showed that the expression of GM-CSF in the pancreas of BALB/c mice greatly enhanced the recruitment and activation of APC within this organ [21]. In addition, it has recently been shown Fig.…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…19 Because hepatosplenomegaly is frequently observed in flaviviral infections, 43,44 and up-regulated GM-CSF and IL-1␤ serum levels correlate with disease severity, 11 GM-M is probably the dominant macrophage subset during flaviviral infection. This argument is supported by the observation that DV-infected M-M did not produce IL-1␤; thus, GM-M seems to play a more important role than M-M in the pathogenesis of DV infection.…”

“…This observation suggests that macrophage differentiation during inflammatory reactions is under the influence of GM-CSF, which can cause massive increase of macrophage population in spleen and induce splenomegaly. 19 Based on these findings, Hamilton 17 suggested that constant level of M-CSF is crucial to maintain M population in a homeostatic and resting condition (denoted as resting M ), whereas the local and temporal increase of GM-CSF during inflammation polarizes M to an inflammatory stage (denoted as inflammatory macrophage). Recently, an epidemiologic study demonstrated that elevated GM-CSF in the plasma of DV patients correlates with the severity of DF/DHF, 11 suggesting that DV infection may switch macrophages from resting to inflammatory status in DV patients and affect the gravity of clinical outcomes.…”