Endothelial cells in the innate response to allergens and initiation of atopic asthma.

Protease-activated receptor 2 (PAR-2), an airway epithelial pattern recognition receptor (PRR), participates in the genesis of house dust mite-induced (HDM-induced) asthma. Here, we hypothesized that lung endothelial cells and proangiogenic hematopoietic progenitor cells (PACs) that express high levels of PAR-2 contribute to the initiation of atopic asthma. HDM extract (HDME) protease allergens were found deep in the airway mucosa and breaching the endothelial barrier. Lung endothelial cells and PACs released the Th2-promoting cytokines IL-1α and GM-CSF in response to HDME, and the endothelium had PAC-derived VEGF-C-dependent blood vessel sprouting. Blockade of the angiogenic response by inhibition of VEGF-C signaling lessened the development of inflammation and airway remodeling in the HDM model. Reconstitution of the bone marrow in WT mice with PAR-2-deficient bone marrow also reduced airway inflammation and remodeling. Adoptive transfer of PACs that had been exposed to HDME induced angiogenesis and Th2 inflammation with remodeling similar to that induced by allergen challenge. Our findings identify that lung endothelium and PACs in the airway sense allergen and elicit an angiogenic response that is central to the innate nonimmune origins of Th2 inflammation.

Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages.

Bone marrow-derived macrophages (BMMs) treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), differentiate into GM-CSF-induced mouse bone marrow-derived macrophages (GM-BMMs) or M-CSF-induced mouse bone marrow-derived macrophages (M-BMMs), which have an M1 or M2 profile, respectively. GM-BMMs produce large amounts of proinflammatory cytokines and mediate resistance to pathogens, whereas M-BMMs produce antiinflammatory cytokines that contribute to tissue repair and remodeling. M-BMMs stimulated with lipopolysaccharide (LPS) are in an antiinflammatory state, with an IL-12(low) IL-10(high) phenotype. However, the regulation of this process remains unclear. Klf10 belongs to the family of Krüppel-like transcription factors and was initially described as a TGF-ß inducible early gene 1. IL-12p40 is upregulated in LPS-stimulated M-BMMs from Klf10-deficient mice, but downregulated during Klf10 overexpression. Klf11, another member of the Krüppel-like factor family, can also repress the production of IL-12p40. Furthermore, Klf10 binds to the CACCC element of the IL-12p40 promoter and inhibits its transcription. We have therefore identified Klf10 as a transcription factor that regulates the expression of IL-12p40 in M-BMMs.

Polycomb antagonizes p300/CREB-binding protein-associated factor to silence FOXP3 in a Kruppel-like factor-dependent manner.

Inducible gene expression underlies the epigenetically inherited differentiation program of most immune cells. We report that the promoter of the FOXP3 gene possesses two distinct functional states: an "off state" mediated by the polycomb histone methyltransferase complex and a histone acetyltransferase-dependent "on state." Regulating these states is the presence of a Kruppel-like factor (KLF)-containing Polycomb response element. In the KLF10(-/-) mouse, the FOXP3 promoter is epigenetically silenced by EZH2 (Enhancer of Zeste 2)-mediated trimethylation of Histone 3 K27; thus, impaired FOXP3 induction and inappropriate adaptive T regulatory cell differentiation results in vitro and in vivo. The epigenetic transmittance of adaptive T regulatory cell deficiency is demonstrated throughout more than 40 generations of mice. These results provide insight into chromatin remodeling events key to phenotypic features of distinct T cell populations.

Early growth response transcription factors and the modulation of immune response: implications towards autoimmunity.

Early Growth Response (EGR) zinc finger transcription factors are induced under diverse mitogenic signals on different cell types such as lymphocytes. Their genetic expression does not require de novo protein synthesis, which suggests its role as immediate response mediators between cell surface receptor signaling and gene expression regulation. EGR factors are involved in modulating the immune response, by means of the induction of differentiation of lymphocyte precursors, activation of T and B cells, as well as their involvement in central and peripheral tolerance. The maturation state, particularly for B cells, and signaling through the T or B cell receptors seems to be quite relevant for the induction of the expression of these transcription factors. EGR-1 functions as a positive regulatory factor for B and T cells mediated by transcriptional regulation of key cytokines and costimulatory molecules, and its interaction with NFAT. On the opposite, EGR-2 and 3 act as negative regulators involved in anergy induction and apoptosis. EGR-2 and 3 deficiency has been related to the development of lupus like disease in murine models. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expansion of effector and activated T cells.

Early growth response transcriptional regulators are dispensable for macrophage differentiation.

Early growth response (Egr) proteins comprise a family of transcriptional regulators (Egr1-4) that modulate gene expression involved in the growth and differentiation of many cell types. In particular, Egr1 is widely believed to have an essential role in regulating monocyte/macrophage differentiation. However, Egr1-deficient mice have normal numbers of functional macrophages, an observation that has led to the hypothesis that other Egr proteins may compensate for Egr1 function in vivo. We examined whether other Egr transcription factors have a functionally redundant role in monocyte/macrophage differentiation. Egr1 and Egr3 expression was found to be induced in myeloid cells when they were differentiated into macrophages by treatment with M-CSF, whereas Egr2 was minimally induced and Egr4 was not detected. In either Egr1/Egr3 or Egr1/Egr2 double homozygous mutant mice, macrophage differentiation and function remained unimpaired. Additionally, the expression of molecules that broadly inhibit Egr function failed to block commitment to the monocytic lineage or inhibit the maturation of monocyte precursors. Finally, several hemopoietic growth factors were found to induce Egr gene expression, indicating that Egr gene expression is not cell lineage specific. Taken together, these results demonstrate that Egr transcription factors are neither essential for nor specific to monocyte/macrophage differentiation.