Toll-Like Receptors in Brain Development and Homeostasis

The experiments reported by Boivin and colleagues complement those discussed in the Perspective, and make a significant contribution to our understanding of the role of TLRs in nervous system repair. Notable advances are the fact that the lesion was a peripheral (sciatic) nerve lesion, in some ways similar to a facial nerve lesion, but inducing locomotor function disability, recovery from which could then be measured. Wallerian degeneration in the lesioned sciatic nerve involves clearance of debris by macrophages, which is both quantifiable and contributes to functional recovery. Similar to the findings of Kigerl et al., deficiencies in both TLR2 and in TLR4 compromised recovery.

Additionally, Boivin et al. show that deficiency in MyD88, the intracellular adaptor molecule that signals downstream of most TLRs, induced even greater compromise of recovery - use of this knockout may be considered conceptually similar to combining both TLR knockouts, of course with additional effect on other receptors that signal through the same adaptor (IL-1β and other TLRs). Interestingly, some responses were not completely ablated by MyD88 deficiency, indicating that pathways of injury response are complex and redundant, as befits such a biologically important process. A distinction from the study by Babcock et al. was that TLR2 deficiency in the sciatic nerve lesion affected macrophage infiltration-- Boivin et al. suggest that one reason for this discrepancy may have to do with participation of TLR2-expressing Schwann cells in response to the peripheral lesion, thus amplifying effects of TLR2 deficiency.

Importantly, Boivin et al. have now done the opposite intervention, assessing the effect of deliberate stimulation of TLR signaling by in vivo administration of TLR2 (zymosan) and TLR4 (LPS) agonists. In both cases macrophage infiltration, clearance of debris and functional recovery were all significantly enhanced. This is a remarkable illustration of the powerful role that TLR signaling plays in nervous system response to injury, and reinforces interest in the endogenous agonists that trigger these responses.

Citations

A. Boivin, I. Pineau, B. Barrette, M. Filali, N. Vallières, S. Rivest, S. Lacroix, Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J. Neurosci.27, 12565-12576 (2007). [Abstract] [Full Text]

K. A. Kigerl, W. Lai, S. Rivest, R. P. Hart, A. R. Satoskar, P. G. Popovich, Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J. Neurochem.102, 37–50 (2007). [PuMed]

A. A. Babcock, M. Wirenfeldt, T. Holm, H. H. Nielsen, L. Dissing-Olesen, H. Toft-Hansen, J. M. Millward, R. Landmann, S. Rivest, B. Finsen, T. Owens, Toll-like receptor 2 signaling in response to brain injury: An innate bridge to neuroinflammation. J. Neurosci.26, 12826–12837 (2006). [Abstract] [Full Text]