|
 |
| REVIEW ARTICLE |
|
| Year : 2016 | Volume
: 2
| Issue : 3 | Page : 126-128 |
|
A polarizing view on posttraumatic brain injury inflammatory response
Susanna Rosi
UCSF Research Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA
| Date of Submission | 07-Aug-2016 |
| Date of Decision | 28-Aug-2016 |
| Date of Acceptance | 29-Aug-2016 |
| Date of Web Publication | 18-Oct-2016 |
Correspondence Address:
Susanna Rosi
UCSF Research Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave., Bld #1, Room #101, 94110, San Francisco, CA
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2394-8108.192517
Traumatic brain injury (TBI) activates the simultaneous proliferation of various pro- and anti-inflammatory molecules. Considering the amount of factors participating, this response is naturally complex. However, there is an increasing trend in neurotrauma research to delineate the injury-induced inflammatory responses within the constraints of in vitro defined macrophage polarization phenotypes “M1” and “M2”. Here, we evaluate research examining the complexity of the inflammatory response that cannot be so easily characterized using this binary nomenclature. TBI is demonstrated to induce a broad spectrum of simultaneous expression responses involving both pro- and anti-inflammatory reactions. Specifically, the research revealed a very heterogeneous parenchymal landscape associated with TBI. The concurrent expression of both “M1” and “M2” phenotypic markers on the microglia/macrophages involved suggests that the polarization phenotypes cannot be neatly defined in this M1/M2 paradigm. Recent studies displaying neurotrauma also report similar conflict with the constraints of this binary categorization of “M1/M2”, demonstrating that microglia/macrophages cannot effectively cross-over to strictly polarized “M1-only” or “M2-only” phenotype. Therefore, the complex signaling events surrounding this response indicate that a binary M1/M2 characterization is not adequate to define inflammatory profile. This paper is a review article. Referred literature in this paper has been listed in the references part. The datasets supporting the conclusions of this article are available online by searching the PubMed. Some original points in this article come from the laboratory practice in our research centers and the authors' experiences. Keywords: Categorization, inflammatory response, M1/M2, phenotype expression, traumatic brain injury
How to cite this article:
Rosi S. A polarizing view on posttraumatic brain injury inflammatory response. Brain Circ 2016;2:126-8 |
| Traumatic Brain Injury Activates a Complex, Broad-Spectrum Inflammatory Response | |  |
Following traumatic brain injury (TBI), neuroinflammation is an axiomatic physiological response. Various cell types proliferate this response via the upregulation and release of soluble cellular components to the proximate tissues.[1],[2] CNS-resident microglia and astrocytes primarily produce these constituents, prolonging the activation of the innate immune response within the brain.[3] Considering the amount of factors and receptors participating, this response is naturally complex. Despite this, many have dedicated their time and efforts to the categorization of the inflammatory response into a “M1” versus “M2” delineation as innate polarization phenotypes. Originally, studies had described innate immune polarization by examining the particular effects of singular stimuli (lipopolysaccharide, interleukin-4, interferon), on the gene expression of the macrophages in vitro.[4] The “M1/M2” terminology later evolved [5] and expanded into subdivisions [6],[7],[8],[9] to appropriately adapt to the constant-changing range of stimuli and gene responses of macrophages in vitro over time. Overall, this effort focused on grouping tissue macrophage responses to corresponding responses of polarized lymphocytes.[5] However, it has been revealed that the polarization states of lymphocytes [10] do not adequately transfer to macrophages, referencing their recognizable plasticity.[11],[12],[13],[14] Martinez and Gordon reiterated these conclusions in a recent review [15] proposing that, in vivo, the inflammatory response associated with disease or injury involves cells reacting to various stimuli concurrently, suggesting these responses involve mixed phenotypes.
Accordingly, we classified the inflammatory response of the brain within the parameters of simultaneous or mixed macrophage phenotypes after TBI. The rodent model displaying moderate TBI [16] was used to characterize the temporal inflammatory profiles following trauma at various succeeding time points. The inflammatory response was examined over ninety subjects covering a wide range of the M1/M2 macrophage inflammatory spectrum, guided by exceptional sources majoring in macrophage polarization.[6],[8],[11],[12],[15],[17],[18],[19],[20],[21] A recent study investigated whether TBI activated a broad-spectrum inflammatory response, involving the expression of both M1 and M2 phenotypes associated with TBI.[22] This simultaneous expression was displayed at many time points following injury, suggesting a common point of differential gene expression. In addition, microglia/macrophages in the area of trauma reflect these responses antigenically by the simultaneous expression of both M1 and M2 phenotypes on the same cell. This high level of complexity and plasticity of parenchymal macrophage responses in TBI questions the efficacy of the dichotomous system, “M1 versus M2,” that poses constraints in defining such responses.
| Simultaneous M1/m2 Profiles Induced by Traumatic Brain Injury | | |
In the study by Morganti et al., they showed that TBI elicited substantial morphological changes in the innate effectors of the surrounding tissue at each time point following injury.[22] Moreover, as a progression of time after trauma, the cells principally responsible for the production of the inflammatory mediators, macrophages/microglia, expressed a mixed phenotype by co-labeling with both polarization markers across three time points; one day, two days, and seven days following injury. The authors next demonstrated that at each time point, TBI initiated significant changes in expression of each analyte for both pro- and anti-inflammatory gene markers. Taken together, these data support the recent reports proposing that macrophages/microglia cannot effectively cross-over to a strictly polarized “M1-only” or “M2-only” phenotype. Rather, these cells display a mixed phenotype as a result of the complex signaling events that occur after injury. As such, these data show that while the macrophage/microglia population profile displays an “activated” appearance, these cells are responding to both pro- and anti-inflammatory milieu concurrently. Moreover, these techniques revealed a very heterogeneous parenchymal landscape associated with TBI, with cells displaying dually labeled “M1/M2” markers alongside “M1” and “M2” cells.
Binary characterization of microglia/macrophages is not sufficient to define inflammatory profile
Despite the complex inflammatory response discovered by microarray [23],[24],[25] and bioinformatics,[16],[26] there is an increasing trend to adopt a binary approach to categorize these reactions based upon decade-old understanding of in vitro-derived stimulus responses of isolated macrophages.[5] However, the findings by Morganti et al. have demonstrated that the polarization phenotypes cannot be neatly delineated in this M1/M2 paradigm, as there is a simultaneous differential expression of both “M1” and “M2” phenotypes in both the microenvironment and within the same cell.[22] Moreover, other models displaying neurotrauma have reported similar conflict with the constraints of the binary categorization of “M1/M2”,[27],[28],[29],[30],[31] even when examining a variety of differentiating factors including time course, species, and injury location (e.g., brain or spinal cord). While the study by Morganti et al. admittedly does not examine every mediator previously reported to represent M1/M2 bias, the subjects studied encompass an everchanging collection of molecular mechanisms, those of which that are frequently used as animal models of neurotrauma. Moreover, as demonstrated in our data, there exists no preferential bias toward or against one polarization phenotype versus the next. This gene expression calls into question the viability of using a single antigenic marker of cell morphology (e.g., Iba1 or F4/80) to determine the inflammatory profile of these cells in a specific population. Therefore, these data show that while the macrophage/microglia population profile displays an “activated” appearance, these cells are responding to both pro- and anti-inflammatory milieu concurrently.
| Conclusion | | |
The recent findings by Morganti et al. align with recent works acknowledging a gap between the in vitro macrophage phenotype modeling and the in vivo tissue trauma response.[22] Surely, these findings are by no means meant to discredit previous studies exploring M1/M2 bias after neurotrauma, recognizing the role of neuroinflammation in the propagation of neuropathopysiology following neurotrauma. Nonetheless, attempting to easily delineate the highly complex molecular mechanisms of an inflammatory response into a dichotomous nomenclature poses too many restrictions to be viable. The simultaneous differential expression of inflammatory status in this current study shows the “polarization” dogma is not applicable to TBI. While we recognize that performing large profiling experiments is not practical for every study, classification of cells (e.g. M1, M2a, M2b, M2c, M2d) depending on few selectively chosen inflammatory markers is not reasonable either in this sense. Rather, defining the roles of these markers by a neuroinflammatory sequela appears as a more pragmatic approach in characterizing the TBI-induced inflammation.
Financial support and sponsorship
R21AG042016 (SR); R21 NS087458 (SR); R21NS096718 (SR).
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Front Neurol 2013;4:30.  |
| 2. | Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, Tan J. The immunology of traumatic brain injury: A prime target for Alzheimer's disease prevention. J Neuroinflammation 2012;9:185. |
| 3. | Gyoneva S, Ransohoff RM. Inflammatory reaction after traumatic brain injury: Therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci 2015;36:471-80. |
| 4. | Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J Exp Med 1992;176:287-92. |
| 5. | Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000;164:6166-73. |
| 6. | Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23-35. |
| 7. | Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 2005;175:342-9. |
| 8. | Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008;8:958-69. |
| 9. | Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol 2010;11:889-96. |
| 10. | Josefowicz SZ. Regulators of chromatin state and transcription in CD4 T-cell polarization. Immunology 2013;139:299-308. |
| 11. | Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat Rev Immunol 2011;11:750-61. |
| 12. | Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014;40:274-88. |
| 13. | Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S, Phatnani HP, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 2013;4:385-401. |
| 14. | Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-ß-dependent molecular and functional signature in microglia. Nat Neurosci 2014;17:131-43. |
| 15. | Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep 2014;6:13. |
| 16. | Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, et al. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci 2015;35:748-60. |
| 17. | Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004;25:677-86. |
| 18. | Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-55. |
| 19. | Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5:953-64. |
| 20. | Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 2011;11:762-74. |
| 21. | Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 2010;10:453-60. |
| 22. | Morganti JM, Riparip LK, Rosi S. Call Off the Dog(ma): M1/M2 polarization Is concurrent following traumatic brain injury. PLoS One 2016;11:e0148001. |
| 23. | Crack PJ, Gould J, Bye N, Ross S, Ali U, Habgood MD, et al. The genomic profile of the cerebral cortex after closed head injury in mice: Effects of minocycline. J Neural Transm (Vienna) 2009;116:1-12. |
| 24. | Shojo H, Kaneko Y, Mabuchi T, Kibayashi K, Adachi N, Borlongan CV. Genetic and histologic evidence implicates role of inflammation in traumatic brain injury-induced apoptosis in the rat cerebral cortex following moderate fluid percussion injury. Neuroscience 2010;171:1273-82. |
| 25. | White TE, Ford GD, Surles-Zeigler MC, Gates AS, Laplaca MC, Ford BD. Gene expression patterns following unilateral traumatic brain injury reveals a local pro-inflammatory and remote anti-inflammatory response. BMC Genomics 2013;14:282. |
| 26. | Helmy A, Antoniades CA, Guilfoyle MR, Carpenter KL, Hutchinson PJ. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury. PLoS One 2012;7:e39677. |
| 27. | Hsieh CL, Kim CC, Ryba BE, Niemi EC, Bando JK, Locksley RM, et al. Traumatic brain injury induces macrophage subsets in the brain. Eur J Immunol 2013;43:2010-22. |
| 28. | Fenn AM, Hall JC, Gensel JC, Popovich PG, Godbout JP. IL-4 signaling drives a unique arginase/IL-1ß+ microglia phenotype and recruits macrophages to the inflammatory CNS: Consequences of age-related deficits in IL-4Ra after traumatic spinal cord injury. J Neurosci 2014;34:8904-17. |
| 29. | Wang G, Zhang J, Hu X, Zhang L, Mao L, Jiang X, et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab 2013;33:1864-74. |
| 30. | Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI, Loane DJ. Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging 2013;34:1397-411. |
| 31. | Turtzo LC, Lescher J, Janes L, Dean DD, Budde MD, Frank JA. Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation 2014;11:82. |
| This article has been cited by | | 1 |
Female and male microglia are not different in the dentate gyrus of postnatal day 10 mice |
|
| Danielle Guez-Barber, Lorianna M. Colon, Dana Raphael, Max A. Wragan, Sanghee Yun, Amelia J. Eisch | | Neuroscience Letters. 2023; : 137171 | | [Pubmed] | [DOI] | | | 2 |
Mesenchymal Stem Cell Therapy: A Potential Treatment Targeting Pathological Manifestations of Traumatic Brain Injury |
|
| Kaige Zhang, Yiming Jiang, Biyao Wang, Tiange Li, Dehao Shang, Xinwen Zhang, Hareram Birla | | Oxidative Medicine and Cellular Longevity. 2022; 2022: 1 | | [Pubmed] | [DOI] | | | 3 |
A review of the pathology and treatment of TBI and PTSD |
|
| Molly Monsour, Dominique Ebedes, Cesario V. Borlongan | | Experimental Neurology. 2022; 351: 114009 | | [Pubmed] | [DOI] | | | 4 |
Microglial Phenotypic Transition: Signaling Pathways and Influencing Modulators Involved in Regulation in Central Nervous System Diseases |
|
| Jiaxin Li,Xinyu Shui,Ruizheng Sun,Lily Wan,Boxin Zhang,Bo Xiao,Zhaohui Luo | | Frontiers in Cellular Neuroscience. 2021; 15 | | [Pubmed] | [DOI] | | | 5 |
Mesenchymal Stem Cell-Induced Anti-Neuroinflammation Against Traumatic Brain Injury |
|
| Blaise Cozene, Nadia Sadanandan, Jeffrey Farooq, Chase Kingsbury, You Jeong Park, Zhen-Jie Wang, Alexa Moscatello, Madeline Saft, Justin Cho, Bella Gonzales-Portillo, Cesar V Borlongan | | Cell Transplantation. 2021; 30: 0963689721 | | [Pubmed] | [DOI] | | | 6 |
Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury |
|
| Haijian Wu,Jingwei Zheng,Shenbin Xu,Yuanjian Fang,Yingxi Wu,Jianxiong Zeng,Anwen Shao,Ligen Shi,Jianan Lu,Shuhao Mei,Xiaoyu Wang,Xinying Guo,Yirong Wang,Zhen Zhao,Jianmin Zhang | | Journal of Neuroinflammation. 2021; 18(1) | | [Pubmed] | [DOI] | | | 7 |
A novel long intergenic non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia |
|
| Nicholas W. Mathy,Olivia Burleigh,Andrew Kochvar,Erin R. Whiteford,Matthew Behrens,Patrick Marta,Cong Tian,Ai-Yu Gong,Kristen M. Drescher,Peter S. Steyger,Xian-Ming Chen,Annemarie Shibata | | Journal of Neuroinflammation. 2021; 18(1) | | [Pubmed] | [DOI] | | | 8 |
DJ-1 Regulates Microglial Polarization Through P62-Mediated TRAF6/IRF5 Signaling in Cerebral Ischemia-Reperfusion |
|
| Tingting Wang,Na Zhao,Li Peng,Yumei Li,Xiaohuan Huang,Jin Zhu,Yanlin Chen,Shanshan Yu,Yong Zhao | | Frontiers in Cell and Developmental Biology. 2020; 8 | | [Pubmed] | [DOI] | | | 9 |
Spleen participation in partial MHC class II construct neuroprotection in stroke |
|
| John Brown,Chase Kingsbury,Jea-Young Lee,Arthur A. Vandenbark,Roberto Meza-Romero,Halina Offner,Cesar V. Borlongan | | CNS Neuroscience & Therapeutics. 2020; | | [Pubmed] | [DOI] | | | 10 |
Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury |
|
| Brooke Bonsack,Sydney Corey,Alex Shear,Matt Heyck,Blaise Cozene,Nadia Sadanandan,Henry Zhang,Bella Gonzales-Portillo,Michael Sheyner,Cesar V. Borlongan | | CNS Neuroscience & Therapeutics. 2020; | | [Pubmed] | [DOI] | | | 11 |
New Therapeutic Avenues of mCSF for Brain Diseases and Injuries |
|
| Vincent Pons,Serge Rivest | | Frontiers in Cellular Neuroscience. 2018; 12 | | [Pubmed] | [DOI] | | | 12 |
Mild focal hypothermia regulates the dynamic polarization of microglia after ischemic stroke in mice |
|
| Liqiang Liu,Xiangrong Liu,Rongliang Wang,Feng Yan,Yumin Luo,Ankush Chandra,Yuchuan Ding,Xunming Ji | | Neurological Research. 2018; : 1 | | [Pubmed] | [DOI] | | | 13 |
Brain-selective mild hypothermia promotes long-term white matter integrity after ischemic stroke in mice |
|
| Li-Qiang Liu,Xiang-Rong Liu,Jing-Yan Zhao,Feng Yan,Rong-Liang Wang,Shao-Hong Wen,Lei Wang,Yu-Min Luo,Xun-Ming Ji | | CNS Neuroscience & Therapeutics. 2018; | | [Pubmed] | [DOI] | | | 14 |
Exercise rehabilitation immediately following ischemic stroke exacerbates inflammatory injury |
|
| Fengwu Li,John T. Pendy,Jessie N. Ding,Changya Peng,Xiaorong Li,Jiamei Shen,Sainan Wang,Xiaokun Geng | | Neurological Research. 2017; 39(6): 530 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
Search Pubmed for