Serum amyloid A (SAA) is an acute phase protein upregulated in the liver after traumatic brain injury (TBI). So far, it has not been investigated whether SAA expression also occurs in the brain in response to TBI. For this, we performed a moderate controlled cortical impact injury in adult male and female mice and analyzed brain, blood, and liver samples at 6 h, 1, 3, and 10 days post-injury (dpi). We measured the levels of SAA in serum, brain and liver by western blot. We also used immunohistochemical techniques combined with in situ hybridization to determine SAA mRNA and protein expression in the brain. Our results revealed higher levels of SAA in the bloodstream in males compared to females at 6 h post-TBI. Liver and serum SAA protein showed a peak of expression at 1 dpi followed by a decrease at 3 to 10 dpi in both sexes. Both SAA mRNA and protein expression colocalize with astrocytes and macrophages/microglia in the cortex, corpus callosum, thalamus, and hippocampus after TBI. For the first time, here we show that SAA is expressed in the brain in response to TBI. Collectively, SAA expression was higher in males compared to females, and in association with the sex-dependent neuroinflammatory response after brain injury. We suggest that SAA could be a crucial protein associated to the acute neuroinflammation following TBI, not only for its hepatic upregulation but also for its expression in the injured brain.
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Anada RP, Wong KT, Jayapalan JJ, Hashim OH, Ganesan D (2018) Panel of serum protein biomarkers to grade the severity of traumatic brain injury. Electrophoresis 39:2308–2315. https://doi.org/10.1002/elps.201700407
Barbierato M, Borri M, Facci L, Zusso M, Skaper SD, Giusti P (2017) Expression and differential responsiveness of central nervous system glial cell populations to the acute phase protein serum amyloid A. Sci Rep 7:12158. https://doi.org/10.1038/s41598-017-12529-7
Bramlett HM, Dietrich WD (2001) Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J Neurotrauma 18:891–900. https://doi.org/10.1089/089771501750451811
Carabias CS et al (2019) Serum amyloid A1 as a potential intracranial and extracranial clinical severity biomarker in traumatic brain injury. J Intensive Care Med. https://doi.org/10.1177/0885066619837913
Catania A, Lonati C, Sordi A, Gatti S (2009) Detrimental consequences of brain injury on peripheral cells. Brain Behav Immun 23:877–884. https://doi.org/10.1016/j.bbi.2009.04.006
Centers for Disease and Prevention (2013) CDC grand rounds: reducing severe traumatic brain injury in the United States. MMWR Morb Mortal Wkly Rep 62:549–552
Chae JJ, Aksentijevich I, Kastner DL (2009) Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol 146:467–478. https://doi.org/10.1111/j.1365-2141.2009.07733.x
Chen ES et al (2010) Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 181:360–373. https://doi.org/10.1164/rccm.200905-0696OC
Chen A et al (2016) Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias. Neurobiol Aging 38:56–67. https://doi.org/10.1016/j.neurobiolaging.2015.10.021
Cogan AM, McCaughey VK, Scholten J (2019) Gender differences in outcomes after traumatic brain injury among service members and veterans. PM R. https://doi.org/10.1002/pmrj.12237
Das M, Mohapatra S, Mohapatra SS (2012) New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation 9:236. https://doi.org/10.1186/1742-2094-9-236
Doran SJ, Ritzel RM, Glaser EP, Henry RJ, Faden AI, Loane DJ (2019) Sex differences in acute neuroinflammation after experimental traumatic brain injury are mediated by infiltrating myeloid cells. J Neurotrauma 36:1040–1053. https://doi.org/10.1089/neu.2018.6019
Dotson AL, Wang J, Saugstad J, Murphy SJ, Offner H (2015) Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke. J Neuroimmunol 278:289–298. https://doi.org/10.1016/j.jneuroim.2014.11.020
Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL (2017) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 54:7567–7584. https://doi.org/10.1007/s12035-016-0245-0
Elovaara I, Maury CP, Palo J (1986) Serum amyloid A protein, albumin and prealbumin in Alzheimer's disease and in demented patients with Down's syndrome. Acta Neurol Scand 74:245–250. https://doi.org/10.1111/j.1600-0404.1986.tb07863.x
Facci L, Barbierato M, Zusso M, Skaper SD, Giusti P (2018) Serum amyloid A primes microglia for ATP-dependent interleukin-1beta release. J Neuroinflammation 15:164. https://doi.org/10.1186/s12974-018-1205-6
Fe Lanfranco M, Loane DJ, Mocchetti I, Burns MP, Villapol S (2017) Combination of fluorescent in situ hybridization (FISH) and immunofluorescence imaging for detection of cytokine expression in microglia/macrophage. Cells Bio Protoc. https://doi.org/10.21769/BioProtoc.2608
Gao W, Lu C, Kochanek PM, Berger RP (2014) Serum amyloid A is increased in children with abusive head trauma: a gel-based proteomic analysis. Pediatr Res 76:280–286. https://doi.org/10.1038/pr.2014.86
Gorevic PD (2013) Amyloid and inflammation. Proc Natl Acad Sci U S A 110:16291–16292. https://doi.org/10.1073/pnas.1315112110
Guo JT, Yu J, Grass D, de Beer FC, Kindy MS (2002) Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. J Neurosci 22:5900–5909
Gyoneva S, Ransohoff RM (2015) Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci 36:471–480. https://doi.org/10.1016/j.tips.2015.04.003
Hinson HE, Rowell S, Schreiber M (2015) Clinical evidence of inflammation driving secondary brain injury: a systematic review. J Trauma Acute Care Surg 78:184–191. https://doi.org/10.1097/TA.0000000000000468
Hsieh CL et al (2013) Traumatic brain injury induces macrophage subsets in the brain. Eur J Immunol 43:2010–2022. https://doi.org/10.1002/eji.201243084
Hughes RN (2007) Sex does matter: comments on the prevalence of male-only investigations of drug effects on rodent behaviour. Behav Pharmacol 18:583–589. https://doi.org/10.1097/FBP.0b013e3282eff0e8
Jang WY et al (2017) Overexpression of serum amyloid a 1 induces depressive-like behavior in mice. Brain Res 1654:55–65. https://doi.org/10.1016/j.brainres.2016.09.003
Kinkley SM, Bagshaw WL, Tam SP, Kisilevsky R (2006) The path of murine serum amyloid A through peritoneal macrophages. Amyloid 13:123–134. https://doi.org/10.1080/13506120600877201
Kisilevsky R (1997) Can deposition of amyloid be prevented in Alzheimer's disease? Ann N Y Acad Sci 826:117–127. https://doi.org/10.1111/j.1749-6632.1997.tb48465.x
Kovacevic A et al (2008) Expression of serum amyloid A transcripts in human bone tissues, differentiated osteoblast-like stem cells and human osteosarcoma cell lines. J Cell Biochem 103:994–1004. https://doi.org/10.1002/jcb.21472
Kuroda T et al (2002) Comparison of gastroduodenal, renal and abdominal fat biopsies for diagnosing amyloidosis in rheumatoid arthritis. Clin Rheumatol 21:123–128. https://doi.org/10.1007/pl00011217
Kuroda T et al (2017) Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis. Amyloid 24:123–130. https://doi.org/10.1080/13506129.2017.1338565
Lane T et al (2017) Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre. Amyloid 24:162–166. https://doi.org/10.1080/13506129.2017.1342235
Lanfranco MF, Mocchetti I, Burns MP, Villapol S (2017) Glial- and neuronal-specific expression of CCL5 mRNA in the rat. Brain Front Neuroanat 11:137. https://doi.org/10.3389/fnana.2017.00137
Liang JS, Sloane JA, Wells JM, Abraham CR, Fine RE, Sipe JD (1997) Evidence for local production of acute phase response apolipoprotein serum amyloid A in Alzheimer's disease brain. Neurosci Lett 225:73–76
Liossi C, Wood RL (2009) Gender as a moderator of cognitive and affective outcome after traumatic brain injury. J Neuropsychiatry Clin Neurosci 21:43–51. https://doi.org/10.1176/jnp.2009.21.1.43
Loram LC et al (2012) Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology 37:1688–1699. https://doi.org/10.1016/j.psyneuen.2012.02.018
McAdam KP, Sipe JD (1976) Murine model for human secondary amyloidosis: genetic variability of the acute-phase serum protein SAA response to endotoxins and casein. J Exp Med 144:1121–1127
Mollayeva T, Mollayeva S, Colantonio A (2018) Traumatic brain injury: sex, gender and intersecting vulnerabilities. Nat Rev Neurol 14:711–722. https://doi.org/10.1038/s41582-018-0091-y
Moore DW, Ashman TA, Cantor JB, Krinick RJ, Spielman LA (2010) Does gender influence cognitive outcome after traumatic brain injury? Neuropsychol Rehabil 20:340–354. https://doi.org/10.1080/09602010903250928
Neumann J et al (2008) Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci 28:5965–5975. https://doi.org/10.1523/jneurosci.0060-08.2008
Ramadori G, Sipe JD, Colten HR (1985a) Expression and regulation of the murine serum amyloid A (SAA) gene in extrahepatic sites. J Immunol 135:3645–3647
Ramadori G, Sipe JD, Dinarello CA, Mizel SB, Colten HR (1985b) Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1. J Exp Med 162:930–942. https://doi.org/10.1084/jem.162.3.930
Ratcliff JJ et al (2007) Gender and traumatic brain injury: do the sexes fare differently? Brain Inj 21:1023–1030. https://doi.org/10.1080/02699050701633072
Sandberg K, Umans JG, Georgetown Consensus Conference Work G (2015) Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research. FASEB J 29:1646–1652. https://doi.org/10.1096/fj.14-269548
Santos-Galindo M, Acaz-Fonseca E, Bellini MJ, Garcia-Segura LM (2011) Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide. Biol Sex Differ 2:7. https://doi.org/10.1186/2042-6410-2-7
Saverino C et al (2016) Rehospitalization after traumatic brain injury: a population-based study. Arch Phys Med Rehabil 97:S19–25. https://doi.org/10.1016/j.apmr.2015.04.016
Scholz M, Cinatl J, Schadel-Hopfner M, Windolf J (2007) Neutrophils and the blood–brain barrier dysfunction after trauma. Med Res Rev 27:401–416. https://doi.org/10.1002/med.20064
Slewa-Younan S, van den Berg S, Baguley IJ, Nott M, Cameron ID (2008) Towards an understanding of sex differences in functional outcome following moderate to severe traumatic brain injury: a systematic review. J Neurol Neurosurg Psychiatry 79:1197–1201. https://doi.org/10.1136/jnnp.2008.147983
Sundelof J et al (2009) Systemic inflammation and the risk of Alzheimer's disease and dementia: a prospective population-based study. J Alzheimers Dis 18:79–87. https://doi.org/10.3233/JAD-2009-1126
Tucker LB, Fu AH, McCabe JT (2016) Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. J Neurotrauma 33:880–894. https://doi.org/10.1089/neu.2015.3977
Tucker LB, Burke JF, Fu AH, McCabe JT (2017) Neuropsychiatric symptom modeling in male and female C57BL/6J mice after experimental traumatic brain injury. J Neurotrauma 34:890–905. https://doi.org/10.1089/neu.2016.4508
Uhlar CM, Whitehead AS (1999a) The kinetics and magnitude of the synergistic activation of the serum amyloid A promoter by IL-1 beta and IL-6 is determined by the order of cytokine addition. Scand J Immunol 49:399–404. https://doi.org/10.1046/j.1365-3083.1999.00515.x
Uhlar CM, Whitehead AS (1999b) Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265:501–523. https://doi.org/10.1046/j.1432-1327.1999.00657.x
Upragarin N, Landman WJ, Gaastra W, Gruys E (2005) Extrahepatic production of acute phase serum amyloid A. Histol Histopathol 20:1295–1307. https://doi.org/10.14670/HH-20.1295
Utagawa A, Truettner JS, Dietrich WD, Bramlett HM (2008) Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats. Exp Neurol 211:283–291. https://doi.org/10.1016/j.expneurol.2008.02.001
Villalba M et al (2012) Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes. Med Microbiol Immunol 201:371–379. https://doi.org/10.1007/s00430-012-0247-0
Villapol S (2016) Consequences of hepatic damage after traumatic brain injury: current outlook and potential therapeutic targets. Neural Regen Res 11:226–227. https://doi.org/10.4103/1673-5374.177720
Villapol S, Byrnes KR, Symes AJ (2014) Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Front Neurol 5:82. https://doi.org/10.3389/fneur.2014.00082
Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ (2015) Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 138:3299–3315. https://doi.org/10.1093/brain/awv172
Villapol S, Loane DJ, Burns MP (2017) Sexual dimorphism in the inflammatory response to traumatic brain injury. Glia 65:1423–1438. https://doi.org/10.1002/glia.23171
Wicker E, Benton L, George K, Furlow W, Villapol S (2019) Serum Amyloid A protein as a potential biomarker for severity and acute outcome in traumatic brain injury. Biomed Res Int 2019:5967816. https://doi.org/10.1155/2019/5967816
Woodcock T, Morganti-Kossmann MC (2013) The role of markers of inflammation in traumatic brain injury. Front Neurol 4:18. https://doi.org/10.3389/fneur.2013.00018
Yang T, Liu YWY, Zhao L, Wang H, Yang N, Dai SS, He FT (2017) Metabotropic glutamate receptor 5 deficiency inhibits neutrophil infiltration after traumatic brain injury in mice. Sci Rep 7:12. https://doi.org/10.1038/s41598-017-10201-8
Yu Y, Liu J, Li SQ, Peng L, Ye RD (2014) Serum amyloid a differentially activates microglia and astrocytes via the PI3K pathway. J Alzheimers Dis 38:133–144. https://doi.org/10.3233/JAD-130818
Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7:22–30. https://doi.org/10.1016/j.nurt.2009.10.016
We thank the master’s degree in Biochemistry and Molecular Biology Program at Georgetown University for the support.
This work was supported by R03NS095038 (SV) grant from the National Institute for Neurological Disorders and Stroke (NINDS), and funds from Houston Methodist Research Institute.
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The authors declare that they have no conflict of interest.
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Soriano, S., Moffet, B., Wicker, E. et al. Serum Amyloid A is Expressed in the Brain After Traumatic Brain Injury in a Sex-Dependent Manner. Cell Mol Neurobiol 40, 1199–1211 (2020). https://doi.org/10.1007/s10571-020-00808-3
- Brain trauma
- Acute phase response
- Neutrophil accumulation