Maintenance Of Myeloid Cells Research Articles

Examining Transcriptomic Differences Underlying Mycosis Fungoides in Skin of Color and White Patients

Abstract Mycosis Fungoides (MF), the most common type of cutaneous T-cell lymphoma, typically presents with an erythematous or dyspigmented rash that can progress to tumors and ulcerations on the skin. MF is more common in skin of color (SOC) patients, where it presents earlier and at a higher T-stage. This has led to poorer prognosis in SOC patients, with the poorest prognosis in African Americans. The pathogenesis regarding this racial disparity remains poorly understood. We compared MF skin samples from SOC and White patients to determine differentially expressed genes and elucidate transcriptomic differences. An immune panel of 343 genes were hybridized to 8 MF SOC and 8 MF White skin samples. The resulting gene signatures were analyzed to determine significant differentially expressed genes. Analysis revealed that SOC has significant downregulation of critical immune response genes involved in the recruitment of immune cells to sites of inflammation, including CCR1, CCR2, and CCR3. Genes involved in ‘chemokine signaling,’ ‘differentiation and maintenance of myeloid cells,’ and ‘cell migration and adhesion,’ were downregulated in SOC MF biopsies as compared to White skin MF biopsies. Furthermore, SOC MF biopsies have a greater abundance of mast cells, whereas White skin MF biopsies have a greater abundance of neutrophils. These transcriptomic differences suggest that MF may have a unique pathogenesis in SOC that involves significant downregulation of the host’s immune response. This potentially provides insight into the presentation of MF at a more advanced stage and aggressive course in SOC as compared to White skin. This insight may facilitate the development of immunotherapies targeted to SOC to address this racial disparity. SD - recipient of the Dermatology Foundation DRSA; JMR - recipient of the Skin of Color Society Reseach Grant; ASB - recipient of the American Skin Association Milstein Research Scholar Award for Melanoma/Non-Melanoma Skin Cancer

Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α.

RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (RαTd) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMαTd/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα+/+ mice expressed RELMα and not Td. Functionally, RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Gene expression analysis indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that RαTd/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4+ T cell effector responses when co-cultured with RELMα+/+ or RELMαTd/Td macrophages, however, RELMαTd/Td macrophages were impaired in their ability to sustain proliferation of FoxP3+ regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3+ cells in the RELMαTd/Td spleens compared to RELMα+/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.

Infiltration of myeloid cells in the pregnant uterus is affected by heme oxygenase-1.

Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1+/-) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1+/+) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation.