Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages

Abstract

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2ϩ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair.

Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment

“…2). Since we previously observed that the response of BMDMs in vitro is predictive of SCI macrophages in vivo 128, we used the genes presented in Fig. 2 as an objective, unbiased, a priori means of phenotyping M1 and M2 macrophages in SCI.…”

“…Proportional areas of macrophages were quantified using techniques developed previously12845. Briefly, the density of labeling above background was quantified using threshold-based measures on one tissue section per animal at the lesion epicenter.…”

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

“…LPS is one of the prototypical stimuli that drives M1 polarization and proinflammatory activity (37). Recent studies have shown that selective TLR2 activation leads to M2 polarization of microglial cells and provides neuroprotective and proregenerative effects (38,39). Because HMGB1 released from dying OLs can bind to both TLR2 and TLR4, it may activate M2-like properties in microglial cells through TLR2 to counterbalance the cytotoxic effects of proinflammatory cytokines stimulated by TLR4.…”

“…Because HMGB1 released from dying OLs can bind to both TLR2 and TLR4, it may activate M2-like properties in microglial cells through TLR2 to counterbalance the cytotoxic effects of proinflammatory cytokines stimulated by TLR4. Thus, it is conceivable that the effects of HMGB1 release from dying neural cells on inflammation could be modulated by the differential expression of pattern recognition receptors in microglial cells (39).…”

The glial scar is more than just astrocytes

“…For example, the authors have completely ignored the expanding immune compartment and make no mention of the cascade of deleterious effects that lesion-derived, highly activated macrophages can inflict upon normal as well as growth stimulated axons. Indeed, we and others have shown that activated macrophages early after injury induce extensive retraction of axons through direct physical contact, specific ligand/receptor interactions and protease secretion (Horn et al, 2008;Busch et al, 2009Busch et al, , 2010Hollis and Zou, 2012;Gensel et al, 2015). This is a powerful repulsive action on axonal outgrowth and the overly simplistic idea that just removing or misaligning the astrocytes would inevitably lead to spontaneous regeneration especially in the presence of such intense inflammation unleashed upon the axons at both acute or chronic stages is, frankly, untenable.…”