Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-β and Engagement of CD85j

Nuñez, Sol Yanel; Ziblat, Andrea; Secchiari, Florencia; Torres, Nicolás I.; Sierra, Jessica Mariel; Iraolagoitia, Ximena L. Raffo; Araya, Romina Elizabeth; Domaica, Carolina Inés; Fuertes, Mercedes; Zwirner, Norberto Walter

doi:10.4049/jimmunol.1700737

Cited by 62 publications

(45 citation statements)

References 34 publications

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“…Anti‐inflammatory cytokines such as TGF‐β also induce NGF expression in human osteoarthritic chondrocytes . M1 macrophages produce proinflammatory cytokines such as TNF‐α and IL‐1β , while M2 macrophages produce anti‐inflammatory cytokines such as IL‐10 and TGF‐β . This piece of evidence suggests that M1‐ and M2‐derived cytokines may play a role in NGF production in IVDs.…”

mentioning

confidence: 94%

Changes in Nerve Growth Factor Expression and Macrophage Phenotype Following Intervertebral Disc Injury in Mice

Nakawaki

Uchida

Miyagi

et al. 2019

Journal Orthopaedic Research

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Nerve growth factor (NGF) is increased in intervertebral discs (IVDs) after disc injury and anti-NGF therapy improves low back pain in humans. Furthermore, M1 and M2 macrophage subtypes play a role in degenerative IVD injury. We examined M1 and M2 macrophage markers and NGF and cytokine expression in IVD-derived cells from control and IVD-injured mice for 28 days following injury. Ngf messenger RNA (mRNA) expression was increased 1 day after injury in injured compared with control mice, and persisted for up to 28 days. Flow cytometric analysis demonstrated that the proportion of F4/80+ CD11b+ cells was significantly increased from 1 day after injury for up to 28 days in injured compared to control mice. mRNA expression of M1 macrophage markers Tnfa, Il1b, and Nos2 was significantly increased 1 day after injury in injured compared to control mice, before gradually decreasing. At 28 days, no significant difference was observed in M1 markers. The M2a marker, Ym1, was significantly increased 1 day after injury in injured compared with control mice, while M2a and M2c markers Tgfb and Cd206 were significantly increased 7, 14, and 28 days after injury. Tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β) stimulated Ngf mRNA and NGF protein expression in IVD cells. Our results suggest that TNF-α and TGF-β may stimulate NGF production under inflammatory and non-inflammatory conditions following IVD injury. As TNF-α and TGF-β are produced by M1 and M2 macrophages, further investigations are needed to reveal the role of macrophages in NGF expression following IVD injury. Our results may aid in developing treatments for IVD-related LBP pathology.

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mentioning

confidence: 94%

Changes in Nerve Growth Factor Expression and Macrophage Phenotype Following Intervertebral Disc Injury in Mice

Nakawaki

Uchida

Miyagi

et al. 2019

Journal Orthopaedic Research

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“…Comparing between MNC trioculture treated with TIMP‐1 neutralizing antibody and trioculture treated with immunoglobulin G (IgG) isotype control, no difference in CML survival was observed. Because it has been suggested that Mϕ suppresses NK activity via TGFβ, we also treated MNC trioculture with TGFβ neutralizing antibody, which showed an observable but insignificant decrease in CML survival compared with IgG isotype control‐treated trioculture (Supplementary figure 16b, gray bars). Taken together, the data suggest that the maintenance of NK mCD16 level is independent of TGFβ and Mϕ TIMP‐1 modulation of MMP–sheddase activity.…”

Section: Resultsmentioning

confidence: 99%

“…However, we found that the Mϕ‐protective effect was contact dependent, suggesting the plausible involvement of membrane‐bound factors on Mϕ in the modulation of NK cytotoxicity and Mϕ‐protective effect on CML. It was reported that Mϕ suppressed NK activity through ligand–receptor interactions via HLAG‐ILT2 and CD48‐2B4, but whether these interactions influence the level of NK mCD16 remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…In the tumor environment, Mϕ more closely resembles the “healing” M2 type, which is protumorigenic and immunosuppressive . In solid tumor environments, it was proposed that Mϕ renders NK cell dysfunctional through soluble factors such as transforming growth factor beta (TGFβ) and prostaglandin E2, and through ligand–receptor interactions via HLAG‐ILT2 and CD48‐2B4 . However, the collaborative role of NK cell and Mϕ in hematological cancers remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Macrophages protect mycoplasma‐infected chronic myeloid leukemia cells from natural killer cell killing

et al. 2020

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Macrophages (M/) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and M/ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (M/ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and M/ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that M/ protects CML from NK attack only when CML was itself mycoplasmainfected and under chronic infection-inflammation condition. We found that the M/-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in M/ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by M/ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating M/mediated retention of NK surface CD16.

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“…It is well known that macrophages can be classified as proinflammatory (M1) or anti‐inflammatory (M2). M2 macrophages express higher levels of HLA‐G than M1 macrophages, resulting in increased LILRB1 expression on NK cells . However, there are no significant differences in LILRB1 expression between M2‐ and M1‐like tumour‐associated macrophages.…”

Section: Lilrb1 Expression On Myeloid Cellsmentioning

confidence: 95%

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

et al. 2019

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Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition.However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.

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Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-β and Engagement of CD85j

Cited by 62 publications

References 34 publications

Changes in Nerve Growth Factor Expression and Macrophage Phenotype Following Intervertebral Disc Injury in Mice

Changes in Nerve Growth Factor Expression and Macrophage Phenotype Following Intervertebral Disc Injury in Mice

Macrophages protect mycoplasma‐infected chronic myeloid leukemia cells from natural killer cell killing

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

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