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Table 1 Summary of the neutrophil-derived mediators and their functions in brain injury

From: Neutrophils in traumatic brain injury (TBI): friend or foe?

Name

Effects

References

IL-1α

#IL-1α expression is closely associated with areas of BBB breakdown and neuronal death at stage of injury

&Induces angiogenesis in brain endothelial cells

[182, 212]

IL-1β

#Localizes with the area of neurons loss and might induce neurons death directly

<Induces astrocytes to secret hemolymphopoietic cytokines (IL-6, IL-8)

[23, 77, 212]

IL-3

&Suppresses secondary degeneration caused by TBI

[213]

IL-4

&Induces M2-polarization of microglia or macrophages

&Promotes white matter integrity and long-term neurological recovery

[26, 214]

IL-6

&Triggers nerve growth factor production in astrocytes

<Might be a prognosis marker of TBI patient

[66, 215]

IL-7

<Contributes to injury-induced reactive gliosis

[216]

IL-9

#Exacerbates excitotoxic brain damage

[217]

IL-10

&IL-10 in traumatic brain and CSF both increases significantly during the first days and may downregulate pro-inflammatory cytokines following traumatic brain damage.

[25]

IL-12

#Highly increased in nonsurvival TBI patients

[215]

IL-16

<Activates microglia and lymphocytes

<Promotes activated microglia and lymphocytes accumulated in microvessels

[218]

IL-17

<Promotes neutrophils invasion

[219]

IL-18

<Peaks at 7 to 14 days after injury and might participate in delayed neuroinflammation

#Induces brain injury in caspase-1-dependent manner

<Induces neutrophils themselves to secrete inflammatory related cytokines

[18, 220, 221]

IL-23

#Leads to brain damage and neurological deficits

[222]

CXCL1

<Recruits circulating-neutrophils into injured brain

[24, 61, 223]

CXCL2

<Peaks at 4 h after TBI, chemotactic for polymorph nuclear leukocytes

[61, 224]

CXCL3

<Promotes neutrophils to migrate across epithelial barriers

[61]

CXCL4

<Induces macrophage to differentiate into a unique phenotype

[225, 226]

CXCL5

#Increases microglia activation as well as BBB damage

#Jeopardizes myelination and promotes astrogliosis

[227]

CXCL8

<Promotes neutrophils to infiltrate into brain parenchyma

[228]

CXCL9

<Promotes lymphocytes to collaborate with mesenchymal stem cells to inhibit T cells’ functions

[229]

CXCL10

<Promotes blood-derived monocytes to accumulate around perivascular vessels

[230, 231]

CXCL11

&Promotes regenerative processes

[230]

CCL2

<Promotes macrophage to infiltrate into parenchyma

<Peaks at 8–12 h after TBI

<Induces transmigration of monocytes and macrophages across BBB

<Activates and induces chemotaxis of T cells and monocytes

[224, 228, 230, 232]

CCL3

<Peaks at 4 h after injury

<Activates and induces chemotaxis of T cells and monocytes

<Recruits CCR2-positive leukocytes to injured brain

[232, 233]

CCL4

<Activates and induces chemotaxis of T cells and monocytes

[232]

CCL17

<Participates in leukocytes recruitment

[234]

CCL22

<Participates in leukocytes recruitment

[234]

G-CSF

&Anti-inflammatory

<Promotes myeloid differentiation and M-CSF secretion

<Reduces T cells’ infiltration

&Prolongs neuronal survival

[175, 235, 236]

M-CSF

#Promotes microglia activation

[236, 237]

GM-CSF

&Suppresses secondary degeneration caused by TBI

[213]

HGF

&Promotes survival reconstruction of specific neurons in response to cerebral injury

[176]

TGF-α

&Induces proliferation, migration, and differentiation of neural stem cells after neurons damage

[238]

TGF-β

&Down-modulates cellular activation

&Blocks inflammatory responses

&Plays a role in nerve regeneration by stimulating nerve growth factor production as well as controlling the astrocytosis and scar formation after injury

[25, 173, 186]

VEGF

&Promotes angiogenesis as well as brain plasticity

&Increases the expression of BDNF in brain endothelial cells

#Enhance the leakage of BBB

[27, 180, 185]

Prokineticin 2

&Participates in constitutive and injury-induced neurogenesis

#Might promote over-inflammation

[239, 240]

TNF-α

#Induces astrocytes to secret hemolymphopoietic cytokines (IL-6, IL-8)

#Mediates PMN-driven neurotoxicity directly

<Early pro-apoptotic effect in neutrophils

[23, 241, 242]

Arginase

&Anti-inflammation

&Augments neurite growth

[26]

BDNF

&Increases cell proliferation

&Upregulates expression of growth factors and induces neurogenesis

[27, 243, 244]

Midkine

&Inhibits apoptosis of neurons

&Promotes neurite extension

[179, 245]

Oncostatin M

#Induces the expression of IL-6 and MMPs

&Protects neurons from excitotoxic injury

[246, 247]

NGF

&Supports neurons survival and nerve growth

[25, 177]

NT4

&Prevents neuronal cell death after TBI

[28, 178]

ROS

#Enhances BBB dysfunction

#Participates in brain energy perturbation (glucose, lactate glycerol)

#Leads to neurons cell death

#Induces microglia activation

[97, 119, 131, 241, 248]

iNOS

<Leads to vasodilatation of blood vessel and improve microcirculation after TBI

&Works as an endogenous antioxidant

<Contributes to protein nitrosylation and nitration

[249, 250]

MMP9

#Breaks down the integrity of BBB

<Promotes infiltration of neutrophils

&Participates in vessel remodeling and angiogenesis

#Mediates PMN-driven neurotoxicity directly

[57, 165, 184, 241, 251]

MPO

<Reflects the infiltration of neutrophils in brain tissue

[189]

Cathepsins

#Contributes to TBI-induced cell death through the programmed cell necrosis and mitochondria-mediated apoptotic pathways

[252]

Defensins

#Penetrates a considerable distance to disrupt the BBB sites

[120]

Cathelicidin

<Attracts peripheral blood neutrophils, monocytes, and T cells

<Promotes IL-1β processing and release

[121, 253]

NE

#Causes cellular stress (astrocytes and microglia) in the injured brain

#Induces acute neurons death

[111, 166, 254]

  1. #Detrimental to the brain tissue and recovery
  2. &Beneficial to the brain tissue and recovery
  3. <Neutral or hard to judge