Macrophage biology in the peripheral nervous system after injury

Abstract

Neuroinflammation has positive and negative effects. This review focuses on the roles of macrophage in the PNS. Transection of PNS axons leads to degeneration and clearance of the distal nerve and to changes in the region of the axotomized cell bodies. In both locations, resident and infiltrating macrophages are found. Macrophages enter these areas in response to expression of the chemokine CCL2 acting on the macrophage receptor CCR2. In the distal nerve, macrophages and other phagocytes are involved in clearance of axonal debris, which removes molecules that inhibit nerve regeneration. In the cell body region, macrophage trigger the conditioning lesion response, a process in which neurons increase their regeneration after a prior lesion. In mice in which the genes for CCL2 or CCR2 are deleted, neither macrophage infiltration nor the conditioning lesion response occurs in dorsal root ganglia (DRG). Macrophages exist in different phenotypes depending on their environment. These phenotypes have different effects on axonal clearance and neurite outgrowth. The mechanism by which macrophages affect neuronal cell bodies is still under study. Overexpression of CCL2 in DRG in uninjured animals leads to macrophage accumulation in the ganglia and to an increase in the growth potential of DRG neurons. This increased growth requires activation of neuronal STAT3. In contrast, in acute demyelinating neuropathies, macrophages are involved in stripping myelin from peripheral axons. The molecular mechanisms that trigger macrophage action after trauma and in autoimmune disease are receiving increased attention and should lead to avenues to promote regeneration and protect axonal integrity.

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

“…This finding suggests that Iba1+ cells are in a physical position to directly influence nociceptive neurons after injury and may potentially contribute to the development of neuropathic pain. Indeed, macrophage‐neuron interactions have been suggested to be crucial for peripheral sensitization and neuropathic pain (Marchand, Perretti, & McMahon, ; Moalem & Tracey, ; Santa‐Cecília et al, ; Vega‐Avelaira et al, ; Zigmond & Echevarria, ). The timing of this migration is also suggestive: Mice have been shown to develop mechanical allodynia during the first 2–3 days after nerve injury (Richner et al, ; Richner, Bjerrum, Nykjaer, & Vaegter, ), which coincides with the formation of the “ring‐like” structures we report here.…”

Advances in the repair of segmental nerve injuries and trends in reconstruction

“…These innate immune cells provide critical phagocytic functions . But additionally, these innate immune cells provide other functions essential to nerve regeneration, including re‐myelination and functional recovery, which are not yet entirely understood, After this Wallerian degeneration process is complete, SCs progressively assume long processes and align on the basal lamina of the intact distal nerve environment (bands of Bungner), providing a permissive growth environment for the regenerating axons that emerge from the proximal nerve stump . As axon growth proceeds from proximal to distal nerve, remyelination of the axons is initiated primarily by axon‐derived neuregulin‐1 signaling through SCs’ ErbB receptors .…”

“…The repair of nerve defects using a pseudosynovial sheath demonstrated that plasma exudates from the proximal and distal nerve stumps fill the empty tube volume, and provide a deposition of extracellular matrix (ECM), including a fibrin matrix, that allows for innate immune system cell migration . While the earliest (<4 days) macrophages are derived from tissue resident macrophages, subsequent macrophages are primarily hematogenous‐derived . Due to the hypoxic nature of this environment, macrophages support a substantial amount of angiogenesis enabling endothelial cell recruitment and vessel formation (Figure 1A).…”

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

“…The immune microenvironment of injured nerves plays a critical role in the regulation of nerve regeneration after injury 5,6 . Debris resulting from degenerated axons and myelin can inhibit axonal regrowth and should be cleared to create a favorable microenvironment for subsequent nerve regeneration 7 . These debris are mainly removed by macrophages, 7,8 which can be increased by activating the toll‐like receptor 4 (TLR4) signaling pathway of the innate immune system via lipopolysaccharide (LPS) 9 .…”

“…Debris resulting from degenerated axons and myelin can inhibit axonal regrowth and should be cleared to create a favorable microenvironment for subsequent nerve regeneration 7 . These debris are mainly removed by macrophages, 7,8 which can be increased by activating the toll‐like receptor 4 (TLR4) signaling pathway of the innate immune system via lipopolysaccharide (LPS) 9 . It has been reported that LPS can accelerate myelin debris clearance during Wallerian degeneration, and promote subsequent axon regeneration via enhanced macrophage recruitment in neurotmesis 8,10 .…”