Background Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. Methods and Results As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed. Conclusions Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.
References
[1]
Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184: 53–68.
[2]
Sieber MW, Claus RA, Witte OW, Frahm C (2011) Attenuated inflammatory response in aged mice brains following stroke. PLoS One 6: e26288.
[3]
Kunz A, Dirnagl U, Mergenthaler P (2010) Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol 24: 495–509.
[4]
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91: 461–553.
[5]
Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276: 13–26.
[6]
Wang X, Feuerstein GZ (2004) The Janus face of inflammation in ischemic brain injury. Acta Neurochir Suppl 89: 49–54.
[7]
Linnartz B, Wang Y, Neumann H (2010) Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. Int J Alzheimers Dis 2010.
[8]
Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3: 445–453.
[9]
Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132: 288–295.
[10]
Neumann H, Takahashi K (2007) Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J Neuroimmunol 184: 92–99.
[11]
Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201: 647–657.
[12]
Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4: e124.
[13]
Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, et al. (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177: 3520–3524.
[14]
Ito H, Hamerman JA (2012) TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells. Eur J Immunol 42: 176–185.
[15]
Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, et al. (2006) Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177: 2051–2055.
[16]
Seno H, Miyoshi H, Brown SL, Geske MJ, Colonna M, et al. (2009) Efficient colonic mucosal wound repair requires Trem2 signaling. Proc Natl Acad Sci U S A 106: 256–261.
[17]
Fisher Y, Nemirovsky A, Baron R, Monsonego A (2010) T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer’s disease. PLoS One 5: e10830.
[18]
Melchior B, Garcia AE, Hsiung BK, Lo KM, Doose JM, et al. (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro 2: e00037.
[19]
Sieber MW, Guenther M, Kohl M, Witte OW, Claus RA, et al. (2010) Inter-age variability of bona fide unvaried transcripts Normalization of quantitative PCR data in ischemic stroke. Neurobiol Aging 31: 654–664.
[20]
Sieber MW, Recknagel P, Glaser F, Witte OW, Bauer M, et al. (2010) Substantial performance discrepancies among commercially available kits for reverse transcription quantitative polymerase chain reaction: a systematic comparative investigator-driven approach. Anal Biochem 401: 303–311.
[21]
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.
[22]
Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, et al. (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 110: 284–294.
[23]
Kim SW, Lee JK (2007) NO-induced downregulation of HSP10 and HSP60 expression in the postischemic brain. J Neurosci Res 85: 1252–1259.
[24]
Bouchon A, Hernandez-Munain C, Cella M, Colonna M (2001) A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194: 1111–1122.
[25]
Noda M, Suzumura A (2012) Sweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis. Int J Alzheimers Dis 2012: 891087.
[26]
Charles JF, Humphrey MB, Zhao X, Quarles E, Nakamura MC, et al. (2008) The innate immune response to Salmonella enterica serovar Typhimurium by macrophages is dependent on TREM2-DAP12. Infect Immun 76: 2439–2447.
[27]
Denes A, Pinteaux E, Rothwell NJ, Allan SM (2011) Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic target. Cerebrovasc Dis 32: 517–527.
[28]
Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, et al. (2002) Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 22: 308–317.
[29]
Fassbender K, Rossol S, Kammer T, Daffertshofer M, Wirth S, et al. (1994) Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci 122: 135–139.
[30]
Minami M, Satoh M (2003) Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci 74: 321–327.
[31]
Vexler ZS, Tang XN, Yenari MA (2006) Inflammation in adult and neonatal stroke. Clin Neurosci Res 6: 293–313.
[32]
Barnum CJ, Tansey MG (2011) The duality of TNF signaling outcomes in the brain: potential mechanisms? Exp Neurol 229: 198–200.
[33]
Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, et al. (2011) Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 10: 471–480.
[34]
Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, et al. (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27: 1941–1953.
[35]
Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, et al. (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196: 290–297.
[36]
Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7: 378–391.
[37]
Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12: 623–635.