Phagocytosis imprints heterogeneity in tissue-resident macrophages

A-González, Noelia; Quintana, Juan A.; García‐Silva, Susana; Mazariegos, Marina S.; Aleja, Arturo González de la; Nicolás-Ávila, José Ángel; Walter, Wencke; Adrover, José M.; Crainiciuc, Georgiana; Kuchroo, Vijay K.; Rothlin, Carla V.; Peinado, Héctor; Castrillo, Antonio; Ricote, Mercedes; Hidalgo, Andrés

doi:10.1084/jem.20161375

Cited by 234 publications

(203 citation statements)

References 66 publications

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“…A). Phagocytosis is a mechanism to imprint distinct pathways of tissue macrophages and has been linked to fibrosis resolution in the liver . MoMF and Kupffer cells both up‐regulate inflammatory cytokines such as Il1b and Tnfa , which have been shown to promote the survival of HSCs and thereby to contribute to liver fibrosis .…”

Section: Resultsmentioning

confidence: 99%

Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Krenkel¹,

Puengel²,

et al. 2018

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Section: Resultsmentioning

confidence: 99%

Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Krenkel¹,

Puengel²,

et al. 2018

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“…Phagocytosis has recently been demonstrated to imprint a distinct anti-inflammatory profile in tissue-resident macrophages and this occurred in part due to phagocytosis of neutrophils 43 . However cardiac tissue resident macrophages were not included in this study so the extent that this occurs in the heart is unknown.…”

Section: Discussionmentioning

confidence: 99%

MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury

DeBerge

Yeap

Dehn

et al. 2017

Circulation Research

177

154

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Rationale: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. Objective : We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. Methods and Results: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, Mertk(CR ) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCII LO CCR2 − (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-β. Mertk deficiency compromised the accumulation of MHCII LO phagocytes, and this was rescued in Mertk(CR ) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. Conclusions: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCII LO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.

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“…iPSDMs derived from this protocol showed higher endocytosis and efferocytosis capacities than PBDMs (Cao et al., 2019), indicating a more tissue‐resident macrophage‐like identity (A‐Gonzalez et al., 2017; Swirski, Robbins, & Nahrendorf, 2016). In addition, it has been shown that iPSDMs can be conditioned by neuronal cells to acquire a microglia identity in vitro (Haenseler et al., 2017; Takata et al., 2017).…”

Section: Commentarymentioning

confidence: 99%

Generation and Functional Characterization of Monocytes and Macrophages Derived from Human Induced Pluripotent Stem Cells

Cao

Hil

Mummery

et al. 2020

CP Stem Cell Biology

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Monocytes and macrophages are essential for immune defense and tissue hemostasis. They are also the underlying trigger of many diseases. The availability of robust and short protocols to induce monocytes and macrophages from human induced pluripotent stem cells (hiPSCs) will benefit many applications of immune cells in biomedical research. Here, we describe a protocol to derive and functionally characterize these cells. Large numbers of hiPSC‐derived monocytes (hiPSC‐mono) could be generated in just 15 days. These monocytes were fully functional after cryopreservation and could be polarized to M1 and M2 macrophage subtypes. hiPSC‐derived macrophages (iPSDMs) showed high phagocytotic uptake of bacteria, apoptotic cells, and tumor cells. The protocol was effective across multiple hiPSC lines. In summary, we developed a robust protocol to generate hiPSC‐mono and iPSDMs which showed phenotypic features of macrophages and functional maturity in different bioassays. © 2020 The Authors. Basic Protocol 1: Differentiation of hiPSCs toward monocytes Support Protocol 1: Isolation and cryopreservation of monocytes Support Protocol 2: Characterization of monocytes Basic Protocol 2: Differentiation of different subtypes of macrophages Support Protocol 3: Characterization of hiPSC‐derived macrophages (iPSDMs) Support Protocol 4: Functional characterization of different subtypes of macrophages

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Phagocytosis imprints heterogeneity in tissue-resident macrophages

Abstract: Macrophages are important for tissue function, and adapt phenotypically to each tissue by factors produced locally. A-Gonzalez et al. now show that phagocytosis of unwanted cells additionally contributes to imprinting macrophage heterogeneity, thus promoting tissue homeostasis.

Cited by 234 publications

References 66 publications

Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury

Generation and Functional Characterization of Monocytes and Macrophages Derived from Human Induced Pluripotent Stem Cells

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