CCR2 deficiency alters activation of microglia subsets in traumatic brain injury

Somebang, Kerri; Rudolph, Joshua; Imhof, Isabella; Li, Luyi; Niemi, Eréne C.; Shigenaga, Judy K.; Tran, Huy; Gill, Thomas M; Lo, Iris; Zabel, Brian A.; Schmajuk, Gabriela; Wipke, Brian T.; Gyoneva, Stefka; Jandreski, Luke; Craft, Michael; Benedetto, Gina; Plowey, Edward D.; Charo, Israel F.; Campbell, James J.; Ye, Chun Jimmie; Panter, S. Scott; Nakamura, Mary C.; Eckalbar, Walter L.; Hsieh, Christine L.

doi:10.1016/j.celrep.2021.109727

Cited by 43 publications

(27 citation statements)

References 70 publications

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“…Whether indeed the high VLCFA levels in X-ALD macrophages amplify their ability to infiltrate the brain parenchyma upon onset of neuroinflammation remains to be clarified. Among the upregulated genes, CCR2 encodes the main chemokine receptor required for monocyte migration from the bone marrow to inflammatory sites and plays a key role in the damaging effects of neuroinflammation following traumatic brain injury [ 64 , 65 ]. Increased levels of CCR2 and CCL7 are not only observed in X-ALD macrophages, but have also been found in inflammatory brain lesions of X-ALD patients [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

Zierfuss

Buda

Villoria-González

et al. 2022

J Neuroinflammation

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Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to inherited dysfunction of the peroxisomal VLCFA transporter ABCD1. In its severest form, X-ALD causes cerebral myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Here, whole transcriptome sequencing of X-ALD macrophages indicated that VLCFAs prime human macrophage membranes for inflammation and increased expression of factors involved in chemotaxis and invasion. When added externally to mimic lipid release in demyelinating X-ALD lesions, VLCFAs did not activate toll-like receptors in primary macrophages. In contrast, VLCFAs provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix-degrading enzymes and chemokine release. Following pro-inflammatory LPS activation, VLCFA levels increased also in healthy macrophages. With the onset of the resolution, VLCFAs were rapidly cleared in control macrophages by increased peroxisomal VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression upon LPS treatment. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.

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Section: Discussionmentioning

confidence: 99%

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

Zierfuss

Buda

Villoria-González

et al. 2022

J Neuroinflammation

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“…Moreover, there is a regulatory interaction between SOCS proteins and IRF7 in a way that SOCS1 and SOCS3, induced by TLR7 in human plasmacytoid dendritic cells, promote IRF7 proteasomal degradation ( 63 ). Interestingly, application of antagonistic human (h)CCR2 small molecule inhibitor after traumatic brain injury to hCCR2 knock-in mice reduced the expression of Irf7 and mitigated loss of cognitive functions, improving disease outcome ( 64 ). A common marker of myeloid cells Itgam (CD11b), listed under the Staphylococcus aureus infection pathway gene set, was overexpressed in the CCR2 hi compared to the CCR2 lo OCP subset.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2hi osteoclast progenitors

et al. 2022

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IntroductionThe existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior.MethodsIn order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation.ResultsA disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis.ConclusionOur approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.

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“…A recent study revealed that CNS-resident macrophages could quickly generate context-dependent subsets, guided by the dynamics of molecule expression during neuroinflammation ( 19 ). Another study found that a deficient C-C chemokine receptor-2 (Ccr2) after TBI will reduce the expression of the IFN-responsive gene (IRF7), which will shape our understanding in finding the targets from the diversity and crosstalk of neuroinflammation ( 30 ). Therefore, permanent changes in the CNS molecular expression may explain the immune heterogeneity observed in patients with TBI.…”

Section: Triggering Signalmentioning

confidence: 99%

Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

Zheng

Lee

et al. 2022

Front. Immunol.

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Traumatic brain injury (TBI) is associated with high mortality and disability, with a substantial socioeconomic burden. With the standardization of the treatment process, there is increasing interest in the role that the secondary insult of TBI plays in outcome heterogeneity. The secondary insult is neither detrimental nor beneficial in an absolute sense, among which the inflammatory response was a complex cascade of events and can thus be regarded as a double-edged sword. Therefore, clinicians should take the generation and balance of neuroinflammation following TBI seriously. In this review, we summarize the current human and animal model studies of neuroinflammation and provide a better understanding of the inflammatory response in the different stages of TBI. In particular, advances in neuroinflammation using proteomic and transcriptomic techniques have enabled us to identify a functional specific delineation of the immune cell in TBI patients. Based on recent advances in our understanding of immune cell activation, we present the difference between diffuse axonal injury and focal brain injury. In addition, we give a figurative profiling of the general paradigm in the pre- and post-injury inflammatory settings employing a bow-tie framework.

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CCR2 deficiency alters activation of microglia subsets in traumatic brain injury

Cited by 43 publications

References 70 publications

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2hi osteoclast progenitors

Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

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