Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.

Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation.

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain.

The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice.

Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages.

Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/α-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via 13C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS-activated macrophages. We also found that type I IFN-driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages.

GM-CSF- and IRF4-Dependent Signaling Can Regulate Myeloid Cell Numbers and the Macrophage Phenotype during Inflammation.

Studies have demonstrated the importance of a GM-CSF→IFN regulatory factor 4 (IRF4)→CCL17 pathway, first identified in monocytes/macrophages, for arthritic pain and disease development. In this study, we further investigated the involvement of this new pathway in shaping the inflammatory response using the zymosan-induced peritonitis (ZIP) model. ZIP (8 mg of zymosan, i.

CSF-1 in Inflammatory and Arthritic Pain Development.

Pain is one of the most debilitating symptoms in many diseases for which there is inadequate management and understanding. CSF-1, also known as M-CSF, acts via its receptor (CSF-1R, c-Fms) to regulate the development of the monocyte/macrophage lineage and to act locally in tissues to control macrophage numbers and function. It has been implicated in the control of neuropathic pain via a central action on microglia.

Epigenetic and transcriptional regulation of IL4-induced CCL17 production in human monocytes and murine macrophages.

Interleukin 4 (IL4) is generally viewed as a Th2 cytokine capable of polarizing macrophages into an anti-inflammatory phenotype, whereas granulocyte macrophage-colony-stimulating factor (GM-CSF) is often viewed as a proinflammatory cytokine with part of this function due to its action on monocytes/macrophages. Paradoxically, these two cytokines act additively to enhance the differentiation of dendritic cells from precursors such as monocytes. One up-regulated marker of an IL4-polarized M2 macrophage is the chemokine (C-C motif) ligand 17 (CCL17), which we have recently reported to be induced by GM-CSF in monocytes/macrophages in an interferon regulatory factor 4 (IRF4)-dependent manner.

Cytokine-Induced Acute Inflammatory Monoarticular Arthritis.

Animal models of arthritis enable us to investigate the pathogenesis of the disease and also to evaluate new therapies. Here we describe two different acute inflammatory monoarticular arthritis models (mBSA/IL1β and mBSA/GM-CSF) providing a more rapid and potentially simplified approach to investigate the pathogenesis.

CCL17 blockade as a therapy for osteoarthritis pain and disease.

Background: Granulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF→Jmjd3→interferon regulatory factor 4 (IRF4)→chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway.

TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17.

TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency.

Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity.

Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated.

G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease.

G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti-G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti-G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective.

Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation.

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo.

Merkel cell carcinoma in patients with long-term ingestion of arsenic.

Merkel cell carcinoma (MCC) is a rare primary neuroendocrine carcinoma of the skin, mostly occurring late in life on sun-exposed body parts. Little is known about the specific etiological factors in the pathogenesis of MCC. A previous report indicated that arsenic exposure might cause MCC, which might be another specific type of skin cancer associated with arsenic exposure.