A macrophage-mediated TNFa signaling axis within peripheral nerves is required for initiation of autoimmune peripheral neuropathy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE180498 | GEO | 2021/11/30
REPOSITORIES: GEO
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Project description:The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.
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Project description:CIDP (chronic inflammatory demyelinating polyneuropathy) is a debilitating immune-mediated neuropathy characterized by progressive weakness and sensory loss. Peripheral nerves from affected patients and mouse models show infiltrating CD4+ T cells, and CD4+ T cells from affected mice are sufficient to transfer neuropathy to immunodeficient recipients, suggesting an important role for CD4+ T cells in disease pathogenesis. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we report that IL-21 expression is highly expressed and a unique feature of terminally-differentiated effector CD4+ T cells within peripheral nerves of neuropathic mice. IL-21-expressing CD4+ T cells are comprised of two transcriptionally distinct, clonally expanded populations, which express genes associated with Tfh and Tph subsets. Remarkably, TCR clonotypes were shared between these two IL-21-expressing populations, suggesting lineage differentiation from a common progenitor. Finally, we demonstrate that IL-21 signaling is required for pathogenic T cell infiltration into peripheral nerves through upregulation of CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings highlight IL-21 signaling, Tfh and Tph differentiation, and CXCR6-mediated cellular localization as key pathogenic pathways and potential therapeutic targets in inflammatory neuropathies.
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Project description:Background: Identifying the immune components that are regulated by a2NTD, a peptide cleaved from the N-terminus of the a2 vacuolar ATPase. Methods: In this study, we used pathway-focused PCR arrays to determine the genes that are regulated in human monocytic cell line, THP-1 after a2NTD stimulation over time. Results: a2NTD up-regulated several cytokines including IL-1 alpha, IL-1 beta, and IL-10. Several chemokines were also upregulated including the MCP and MIP families. Conclusion: We believe a2NTD to be an immune modulator made by tumor cells that aid in preventing immune surveillance by up-regulating proteins in monocytes that are both pro-and anti-inflammatory in nature. The Human Inflammatory Response and Autoimmunity RTM-BM-2 ProfilerM-bM-^DM-" PCR Array profiles the expression of 84 key genes involved in autoimmune and inflammatory immune responses. It represents the expression of inflammatory cytokines and chemokines as well as their receptors. It also contains genes related to the metabolism of cytokines and involved in cytokine-cytokine receptor interactions. Thoroughly researched panels of genes involved in the acute-phase response, inflammatory response, and humoral immune responses are represented as well. Using real-time PCR, you can easily and reliably analyze expression of a focused panel of genes related to inflammatory and autoimmune responses with this array.
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Project description:The innate immune system is finely tuned to enable rapid response to pathogenic stimuli but keep quiescent during tissue homeostasis.Balance of activating and inhibitory signaling sets a threshold for immune activation. Signal regulatory protein (SIRPa) is an immune inhibitory receptor expressed by myeloid cells and interacts with CD47 to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPa and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether therapeutic SIRPa receptor agonism could restrain excessive autoimmune inflammation in the context of autoimmunity. Here, we reported that increased neutrophil- and monocyte-associated genes including SIRPA in inflamed tissues biopsies of rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA in colonic biopsies is associated with treatment refractory ulcerative colitis patients. We next identified a novel agonistic anti-SIRPa antibody that exhibited potent anti-inflammatory effects in reducing neutrophil and monocytes chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPa agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis through reducing neutrophils and monocytes in tissues. Our work provides a proof-of-concept for SIRPa receptor agonism for suppressing excessive innate immune activation and autoimmune inflammatory therapeutic treatment
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