IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Celik, Melih Ö.; Łabuz, Dominika; Keye, Jacqueline; Glauben, Rainer; Machelska, Halina

doi:10.1172/jci.insight.133093

Cited by 91 publications

(83 citation statements)

References 68 publications

(107 reference statements)

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“…M2 macrophages were then generated in the presence of 50 ng/mL macrophage colony-stimulating factor (M-CSF) with the percentage of spindle-like cells at 63.25% ± 8.85% (n = 4). To evaluate the ACE2 expressions on macrophages, M2 macrophages were activated by the treatment with lipopolysaccharide (LPS) [12] and interleukin-4 (IL-4) respectively [22]. Phase contrast image showed significant differences in the morphology between two groups ( Figure 4B).…”

Section: High Expression Of Ace2 On the Activated Type 1 Macrophagesmentioning

confidence: 99%

High expression of angiotensin-converting enzyme-2 (ACE2) on tissue macrophages that may be targeted by virus SARS-CoV-2 in COVID-19 patients

Song

et al. 2020

Preprint

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Angiotensin-converting enzyme-2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects host cells, causing the development of the new coronavirus infectious disease (COVID-19). To better understand the pathogenesis of COVID-19 and build up the host anti-viral immunity, we examined the levels of ACE2 expression on different types of immune cells including tissue macrophages. Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood-derived immune cells including CD4+ T, CD8+ T, activated CD4+ T, activated CD8+ T, CD4+CD25+CD127low/- regulatory T cells (Tregs), Th17 cells, NKT cells, B cells, NK cells, monocytes, dendritic cells (DCs), and granulocytes. Additionally, there was no ACE2 expression (< 1%) found on platelets. Compared with interleukin-4-treated type 2 macrophages (M2), the ACE2 expression was markedly increased on the activated type 1 macrophages (M1) after the stimulation with lipopolysaccharide (LPS). Immunohistochemistry demonstrated that high expressions of ACE2 were colocalized with tissue macrophages, such as alveolar macrophages found within the lungs and Kupffer cells within livers of mice. Flow cytometry confirmed the very low level of ACE2 expression on human primary pulmonary alveolar epithelial cells. These data indicate that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS-CoV-2 infection and therefore need to be considered for the prevention and treatment of COVID-19.

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Section: High Expression Of Ace2 On the Activated Type 1 Macrophagesmentioning

confidence: 99%

High expression of angiotensin-converting enzyme-2 (ACE2) on tissue macrophages that may be targeted by virus SARS-CoV-2 in COVID-19 patients

Song

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…55 Alternatively, perineural injected IL-4 treatment attenuated neuropathic pain in a dose-dependent fashion in models of neuropathic pain. 64 IL-4 treatment was also associated with increased M2 macrophage populations in the affected nerve. Interestingly, Celik et al 64 reported IL-4-induced M2 macrophages produced increased levels of opioid peptides compared to untreated groups, unveiling a potential mechanism whereby IL-4 treatment reduces neuropathy-associated pain.…”

Section: The Potential Of Exogenous Il-4 As a Therapymentioning

confidence: 87%

“…64 IL-4 treatment was also associated with increased M2 macrophage populations in the affected nerve. Interestingly, Celik et al 64 reported IL-4-induced M2 macrophages produced increased levels of opioid peptides compared to untreated groups, unveiling a potential mechanism whereby IL-4 treatment reduces neuropathy-associated pain. Compared to the previously discussed systemic IL-4 studies, the findings here carry greater relevance for applications to treat PNI.…”

Section: The Potential Of Exogenous Il-4 As a Therapymentioning

confidence: 87%

The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries

Daines

Schellhardt

Wood

2021

Neurorehabil Neural Repair

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Following traumatic peripheral nerve injury, adequate restoration of function remains an elusive clinical goal. Recent research highlights the complex role that the immune system plays in both nerve injury and regeneration. Pro-regenerative processes in wounded soft tissues appear to be significantly mediated by cytokines of the type 2 immune response, notably interleukin (IL)-4. While IL-4 signaling has been firmly established as a critical element in general tissue regeneration during wound healing, it has also emerged as a critical process in nerve injury and regeneration. In this context of peripheral nerve injury, endogenous IL-4 signaling has recently been confirmed to influence more than leukocytes, but including also neurons, axons, and Schwann cells. Given the role IL-4 plays in nerve injury and regeneration, exogenous IL-4 and/or compounds targeting this signaling pathway have shown encouraging preliminary results to treat nerve injury or other neuropathy in rodent models. In particular, the exogenous stimulation of the IL-4 signaling pathway appears to promote postinjury neuron survival, axonal regeneration, remyelination, and thereby improved functional recovery. These preclinical data strongly suggest that targeting IL-4 signaling pathways is a promising translational therapy to augment treatment approaches of traumatic nerve injury. However, a better understanding of the type 2 immune response and associated signaling networks functioning within the nerve injury microenvironment is still needed to fully develop this promising therapeutic avenue.

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“…IL-4 administration further resulted in a long-lasting attenuation of neuropathy-induced mechanical hypersensitivity after discontinuing treatment. Confirming the importance of M2 macrophage-secreted opioids, IL-4-induced analgesia was decreased after neutralizing opioid peptides or blocking opioid receptors at the injured nerves ( 68 ). These studies indicate that M2 polarized macrophages may regulate pain perception by modulation of the opioid system.…”

Section: Macrophages Alleviate Pain Via the Opioid System And Anti-inmentioning

confidence: 92%

Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain

Bethea

Fischer

2021

Front. Immunol.

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Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain.

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IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Cited by 91 publications

References 68 publications

High expression of angiotensin-converting enzyme-2 (ACE2) on tissue macrophages that may be targeted by virus SARS-CoV-2 in COVID-19 patients

High expression of angiotensin-converting enzyme-2 (ACE2) on tissue macrophages that may be targeted by virus SARS-CoV-2 in COVID-19 patients

The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries

Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain

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