Introduction

Bacterial meningitis is a life-threatening disease associated with long-term cognitive impairment in many survivors [1, 2]. Replication of bacteria within the subarachnoid space occurs concomitantly with the release of their compounds, such as peptidoglycan, lipoteichoic acid (a constituent of the cell wall of Gram-positive bacteria), flagellin (a protein in bacterial flagella), lipopolysaccharide (LPS) (a constituent of the cell wall of Gram-negative bacteria), DNA, and cell wall fragments. These compounds are all referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs are recognized by pattern-recognition receptors (PRRs), which are the pivotal components of the innate immune system [3, 4].

The immune system responds to an infection when microbial pathogens are recognised by antigen-presenting cells. This recognition occurs via the binding of PAMPs to PRRs on antigen-presenting cells such as toll-like receptors (TLRs), RIG-I-like receptors (RLRs), c-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and intra-cytosolic DNA sensors [4, 5]. The interaction between PAMPs and PRRs promotes the release of mediators, including cytokines and chemokines that propagate and regulate the response necessary to remove invasive microorganisms [6]. Innate immune cells are also triggered by endogenous constituents that are normally released from damaged cells including nucleic acids, cytochrome c, uric acid crystals, adenosine 5′-triphosphate (ATP), S100 molecules, histones, heat shock protein (HSP), and high mobility group box-1 protein (HMGB-1). These molecules are known as damage-associated molecular patterns (DAMPs) [7, 8]. Microglia can be activated by many stimuli including PAMPs, DAMPs, or pro-inflammatory mediators to produce cytokines, chemokines, and reactive oxygen and nitrogen species which together are involved in eliminating the invading microorganism. Thus, damage to the central nervous system (CNS) during bacterial meningitis commonly involves pathogenic mechanisms of both bacteria and the innate immune host response [9, 10].

Morphological States and Functions of Microglia

Microglia are the resident macrophages of the CNS parenchyma, they originate from hematopoietic stem cells, and differ from astrocytes in their function, origin, pattern of gene expression and morphological characteristics [11]. Resting microglia morphology exhibits ramified branches that emerge from the cell body and connects with surrounding neurons and glial cells. The extensive surface area allows the microglia to assess and control changes in their environment [12]. Stence and his colleagues (2001) studied the dynamics of microglial cell activation from rat brain tissue slices. The microglia cells converted from a resting ramified morphology to an amoeboid form within several hours in vitro after mechanical injury. The authors suggested that the ramified branches of resting microglia would be incapable of phagocytosis [13]. Another study conducted by Yamada and Jinno (2013) classified reactive microglia into four groups, types I-IV. Type I microglia cells were similar to ramified microglia in a resting state. Type II microglia cells exhibited small cell bodies with thin and short processes. Type III microglia cells were hypertrophied with short thick processes. Type IV “bushy” cells exhibited the greatest process density [14].

Microglia cells maintain cellular, synaptic, and myelin homeostasis during development, normal function of the CNS, and in response to CNS injury. Thus, microglia have been shown to mediate a myriad of aspects of neuroinflammation, including recognition of pathogens bound to MHC for activation of T lymphocytes, phagocytosis, cytotoxicity through production of cytokines, and secretion of glutamate, aspartate, reactive oxygen, and nitrogen species. Additionally, one of the functions of these cells is CNS repair through the removal of cell debris which facilitates plasticity and synaptogenesis [15]. Activated microglia comprises heterogeneous cells that modify their phenotype depending on the type of stimulus and environment [12].

CX3C chemokine CX3CL1 (fractalkine), are found in brain tissue, particularly in neurons and microglia. Microglia binds to CX3CL1 through CX3CR1. CX3CL1 is responsible for many microglial functions including migration, proliferation, inhibition of Fas ligand-induced cell death and glutamate-induced neurotoxicity, and inhibition of pro-inflammatory cytokine production. Therefore, CX3CL1 has neuroprotective functions against activated microglia-induced neurotoxicity [16].

These various functions are associated with M1 and M2 phenotypes and their multiple receptors that can induce different signaling cascades involved in chemotaxis, phagocytosis, and the production of numerous neurotoxic and anti-inflammatory mediators. Microglial cells polarized to the M1 phenotype are considered to be in a pro-inflammatory state, whereas microglia of the M2 has anti-inflammatory properties. In addition, Mox macrophage that is distinct from conventional M1 or M2 macrophage phenotype induced by oxidized phospholipids and nitrosylated fatty acids. Mox macrophages present elevated levels of reactive oxygen species and heme oxygenase-1, and the transcription factor nuclear erythroid 2-related factor 2 (NRF2) [17, 18]. M1 and M2 surface markers and mediator synthesis are demonstrated in Tables 1, 2, and 3 [33].

Table 1 Gene markers in microglia
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Table 2 Protein markers in microglia
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Table 3 Receptors and agonists in microglia
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Microglia Phenotype 1 Activation and Signaling

Several receptors can trigger the M1 phenotype such as TLRs, RLRs, CLRs, NLRs, the receptor for advanced glycation end products (RAGE), P2X purinergic receptor (P2XR), tumor necrosis factor receptor (TNFR), and macrophage-colony-stimulating factor receptor (CSF1R) as shown in Fig. 1.

Fig. 1
figure 1

M1 and M2 phenotypes and their receptors. During bacterial meningitis, the microglia can be activated by peptidoglycan, lipoteichoic acid, lipopolysaccharide (LPS), and pneumolysin which are pathogen-associated molecular patterns (PAMPs), cytokines, and by damage-associated molecular patterns (DAMPs), such as ATP, heat shock protein (HSP), and high-mobility group box 1 protein (HMGB1)

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TLR signaling complexes generally use an intracellular adapter protein, known as myeloid differentiation factor 88 (MyD88), and a so-called TIR domain-containing adaptor protein which induces IFNβ (TRIF) [34]. MyD88 connects to the TLRs by interaction between TIR domains. After being triggered, receptor-associated kinase (IRAK)-4, IRAK-1, and receptor-associated factor (TRAF)-6 are attracted to the receptor, which induces the union of IRAK-1 and MyD88 by way of the death domains. IRAK-4 transduces inflammatory signals activating IRAK-1 followed by IRAK-2 [35]. The signals are then transmitted to the TRAF6 protein complex which converts factor-β-activated kinase-1 (TAK)-1 into a reactive form. The TAK-1 phosphorylates I-kappa B kinase complex (IKK) leading to the activation of the transcription factor nuclear factor-kappa B (NF-κB) [36]. In experimental meningitis, MyD88-deficient mice had decreased interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 2 (MIP2) in the CNS. Nevertheless, MyD88 deficiency was associated with worsening of disease progression along with severe bacteremia [37]. Another intracellular adapter protein, TIR-domain-containing adapter-inducing interferon-β (TRIF) in microglia, transmits a signal from TLR-3 and TLR-4. This signal activates NF-κB and interferon-regulatory factor 3 (IRF-3) leading to the production of pro-inflammatory mediators and type I interferons (IFN) [11, 38]. These transcription factors are capable of serving as activators and promoters of many pro-inflammatory genes, including genes expressed by the M1 phenotype [11, 39]. They are also crucial transcriptional activators of various genes involved in the pathogenesis of meningitis [40, 41].

The detection of various pathogens and DAMPS is mediated by a family of cytosolic proteins called the NOD-like receptors (NLR) [42]. After the recognition of bacterial peptidoglycan, the NOD1 and 2 receptors recruit the receptor-interacting protein-2 (RIP-2), as well as cellular inhibitors of apoptosis (cIAP2) and the X-linked inhibitor of apoptosis protein (XIAP). This complex further activates the TAK1/TAB1/TAB2/TAB3 and IKK complex, which phosphorylates IKB resulting in the release of the transcription factor NF-κB and MAPK. Furthermore, these transcription factors translocate from the nucleus and induce the transcription of IL-1 cytokines [43, 44]. Rodents that were found to lack NOD1 were more susceptible to early pneumococcal sepsis and Gram-positive microorganisms [45]. In vitro, primary murine glia with NOD2 mediated an increased inflammatory response to Streptococcus pneumoniae [46].

The inflammasome is a large molecular platform that detects pathogenic microorganisms, the exotoxin pneumolysin, bacterial DNA, ATP, membrane disruption (for bacterial toxins and ATP), or phagocytised particles. The inflammasome plays a role in innate immunity by contributing to the production of pro-inflammatory cytokines [47]. The NLRP3 inflammasome is composed of nucleotide-binding and oligomerization domain NOD-like receptors (NLRs), apoptosis-associated speck-like protein containing a CARD (ASC) adaptor, and pro-caspase-1. The NLRP3 inflammasome converts proteolytic caspase-1 into a reactive form. Caspase-1 induces the maturation of two powerful cytokines, IL-1β and IL-18 [48]. Intracisternal administration of recombinant IL-1β in rats induced neutrophil migration into the CSF and resulted in the disruption of the blood-brain barrier (BBB) [49]. Moreover, IL-1 receptor type 1 gene-deficient mice had increased mortality and impaired host defense against pneumococcal meningitis [50]. IL-18 gene-deficient mice were found to have decreased inflammatory infiltrate around the meninges and decreased cytokine and chemokine concentrations in brain tissue resulting in suppressed inflammatory response during pneumococcal meningitis [51].Thus, in experimental pneumococcal meningitis, the ASC or NLRP3 knockout mice had a decreased clinical severity score and brain inflammation [52].

Microglial cells also express P2X receptors that are purinergic receptors and belong to the family of trimeric ion channels which are regulated by extracellular ATP [53]. High levels of ATP are released from necrotic cells during bacterial meningitis. The ATP binds to the P2X receptors, activating the NLRP3 inflammasome and inducing the transcription of pro-inflammatory mediators [48], as shown in Fig. 2.

Fig. 2
figure 2

Classical and alternative microglial activation. The M1 phenotype can be activated through TLRs, RLRs, CLRs, NLRs, HMGB-1, histone, and ATP. TLR-2 and 4 commonly use an intracellular adapter protein myeloid differentiation factor 88 (MyD88) with subsequent release and nuclear translocation of NF-κB leading a production of pro-inflammatory cytokines and reactive oxygen species. ATP binds to the P2XR activating the NLRP3 and inducing the transcription of pro-inflammatory mediators. The M2 phenotype can be activated through IL-10 that leads to 17β-hydroxysteroid dehydrogenase type 14 (17β-HSD14). IL-10-IL-10R activates the phosphorylation of the receptor-Janus Kinase-1 (JAK-1), tyrosine kinase-2, and subsequently transcription of signal transducer and activator of transcription-3 (STAT-3) increasing anti-apoptotic and anti-inflammatory mediators. IL-4 increased TGFβ2 and induces upregulation of arginase 1 (Arg1) and chitinase-3-like protein 3 (Ym1)

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RAGE is an important receptor that recognizes DAMPs in microglia [54]. After RAGE binds with its ligands, oxidative stress is increased, contributing to neuroinflammation by upregulation of NF-κB [55]. In vitro, RAGE through HMGB1 mediates chemotaxis, differentiates immune cells, and upregulates TLR4 and RAGE receptors on cell-surface [54].

The CSF1R is a regulator of myeloid lineage cells. The inhibition of CSF1R resulted in the elimination of 99 percent of all microglia within the brain of adult mice, demonstrating that microglia cells in the adult brain are dependent on CSFR1 signaling [56]. Recognition of IL-34 by CSF1R promotes the development of microglial cells [57]. In contrast, IL-34-deficient mice presented a decrease in microglia cells [58].

Microglia Phenotype 2 Activation and Signaling

The M2 phenotype is associated with the capacity to downregulate inflammation and promote tissue repair. Several cytokines, such as IL‑10, IL‑4, IL‑6, and transforming growth factor beta (TGF-β) are produced by M2 phenotype which consequently can suppress the M1 phenotype (Fig. 1). The general M2 phenotype has different pathways according to its sub-phenotypes: M2a, M2b, or M2c [59, 60].

M2a phenotype is designed for phagocytosis, and it is induced by IL-4, IL-13, chitinase 3-like 3 (YM1), and arginase-1 (Arg1) [61]. Different markers have been identified as M2a specific, such as the enzymes Arg1 and FIZZ1 (found in inflammatory zone 1) [62]. Microglia skewed to the M2b phenotype clears the reactive oxygen and nitrogen species released during M1 activation. This phenotype expresses the IL-10 and CCL1, and is skewed by immune complexes and TLR or IL-1R agonists. The M2c phenotype is responsible for tissue remodeling and repair. This phenotype is induced by IL-10, TGF-β, or glucocorticoid hormones and expresses CCL16, CCL17, CCL18, CXCL13, CCR2, and CCR5 [15, 62, 63]. It is of interest that polarization of microglia to the M1 state is associated with a decrease in neurotrophic factor synthesis including BDNF, whereas neurotrophic factor expression is upregulated when microglia have acquired the M2 phenotype [59, 60].

TGF-β plays an important role as an anti-inflammatory cytokine. In microglia, this cytokine inhibits phagocytosis and the production of TNF-α, IL-1, and IL-6 [64]. In vitro, treatment of primary microglia with TGF-β resulted in upregulation of the IL4 receptor, showing that TGF-β increases the capacity of microglia for IL-4 signals. Likewise, IL-4 treatment increased the expression and secretion of TGF-β2 in microglia culture [65]. IL-4 treatment also induces upregulation of arginase 1 (Arg1) and chitinase-3-like protein 3 (Ym1) [65, 66]. Arg1 inhibits nitric oxide (NO) by competing with iNOS because both utilize l-arginine as a substrate [67].

IL-10 is probably the most important anti-inflammatory cytokine used for limiting immune reactions [68]. The biological functions of IL-10 are activated via two receptor chains, IL-10R1 and IL-10R2. This further phosphorylates the receptor-Janus Kinase-1 (JAK-1) and tyrosine kinase-2. This phosphorylation subsequently activates signal transducer and activator of transcription-3 (STAT-3), increasing the expression of anti-apoptotic and anti-inflammatory mediators [69, 70]. Thus, a role of IL-10 is the inhibition of TNF-α, IL-1β, and colony-stimulating factor (GM-CSF) [71, 72]. IL-10 also upregulates the expression of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xl) factors and downregulates pro-apoptotic factors such as cytochrome-c, caspase-3, and Bax [72]. Another way that IL-10 could suppress the M1-like activation state in microglia could be through 17β-hydroxysteroid dehydrogenase type 14 (17β-HSD14) expression. Moreover, 17β-HSD14 mediates the transformation of dehydroepiandrosterone (DHEA) to 5-androstene-3β,17β-diol, which is an anti-inflammatory ligand of estrogen receptor-β (ERβ) [11], (Fig. 2).

Microglial Activation by Bacterial Meningitis

During bacterial meningitis, resident macrophages, astrocytes, glial cells, and endothelial cells can produce cytokines, chemokines, and other pro-inflammatory mediators in response to infection. This intense inflammatory response contributes to neuronal damage and can be fatal for patients [73, 74]. The concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10, and IFN-γ are normally enhanced in cerebrospinal fluid (CSF) of patients with bacterial meningitis [75]. In a study of 48 patients with bacterial meningitis, CSF levels of TNF-α correlated with BBB disruption and neuronal damage [76]. Our knowledge of the pathophysiology of bacterial meningitis is based on patient observation and experimental models. In animal models, TNF-α and IL-1β are produced in the hippocampus and cortex during the first 6 to 24 h after meningitis [77, 78]. The treatment with anti-TNF-α antibody blocked the disruption of the BBB and the entrance of circulatory S. pneumoniae into the brain of rats, demonstrating that TNF-α has an important role in regulating the BBB [79]. However, TNF-α deficient mice had stronger deficits in spatial memory and increased mortality [80].

In response to invasive microorganisms and pro-inflammatory cytokines, polymorphonuclear leukocytes and other immunocompetent cells are attracted and activated in the brain. This reaction produces reactive oxygen species such as superoxide anion (O2 −) and NO, thereby causing the formation of peroxynitrite (ONOO−) [81]. Interaction of ONOO− with biomolecules such as proteins, lipids, and nucleic acid leads to several cytotoxic events including mitochondrial dysfunction and triggering of cell death. Direct nitration and oxidation of invading microorganisms can also lead to destruction of the microorganism [82]. In patients with bacterial meningitis, elevated levels of nitrotyrosine have been detected in the CSF [83]. In vitro, Matata et al. have shown that the production of cytokines by human mononuclear cells is regulated by ONOO− in a NF-κB-dependent manner [84]. Furthermore, in plasma and CSF of patients with acute bacterial meningitis, the enzymatic antioxidants glutathione and superoxide dismutase levels are usually decreased while the malondialdehyde, nitrite, and protein carbonyl levels are elevated, providing evidence for the production of oxidative stress [4, 85, 86]. The increase of reactive oxygen species and decrease of antioxidant defense are found in experimental meningitis. For example, in neonatal meningitis caused by Streptococcus agalactiae, lipid peroxidation and protein carbonyl levels were elevated in the hippocampus [78]. Additionally, oxidative stress was present in the cortex and hippocampus of adult rats affected by pneumococcal meningitis [87]. Moreover, the complex I activity of mitochondrial respiratory chain was inhibited in striatum, hippocampus, and cerebellum after bacterial meningitis [88].

Thus, antioxidants and NOS inhibitors in experimental bacterial meningitis could be a target to prevent neuronal damage. Adjuvant therapy with an ONOO− scavenger decreased leukocyte levels in the CSF, reduced IL-1β and macrophage inflammatory protein 2 (MIP-2) levels in the rat brain [89], and prevented long-term cognitive impairment in experimental pneumococcal meningitis [90]. The activation of microglia is represented by an increased expression of Griffonia simplicifolia isolectin-B4 (GSA-IB4) and ionized calcium binding adaptor molecule 1 (Iba1) in the CA2 region of the hippocampus of rats. This increase coincided with an intense production of TNF-α, IL-1β, and IL-6 and oxidative damage in experimental Klebsiella pneumoniae meningitis [25].

Thus, bacterial meningitis leads to an increase in neutrophil cerebral penetration, a pro-inflammatory state of microglia, oxidative and nitrosative stress production, and subsequently mitochondrial dysfunction, apoptosis, and necrosis resulting in neuronal dysfunction.

Microglial Activation by DAMPs from Bacterial Meningitis

Bacterial meningitis is accompanied by the release of DAMPs, which mediates the inflammatory response and often causes cell injury. In the CSF of pediatric patients with meningitis, HMGB1 (a nuclear protein that is passively released by stressed or damaged cells) has been detected [91]. This protein is recognized by TLR2, TLR4, and RAGE (receptor for advanced glycation end products) further activating the microglial classical pathway and acting as the main propagator of inflammation in pneumococcal meningitis [11, 19]. Under conditions of stress, other molecules such as the intracellular HSPs are also released by the cell provoking the activation of the immune system, many of which have been identified in the CSF of patients with bacterial meningitis [7]. Among the elevated intracellular chaperones were the HSP70 and HSP72 [91, 92]. However, recent data showed that overexpression of HSP70 was associated with anti-inflammatory properties in animal models and in vitro through inhibition of NF-κB. Also, using models of cerebral ischemia-like injury, the overexpression of HSP70 was associated with increased expression of the anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2), and decreased apoptotic cell death. This proposed mechanism may play a possible role in suppression of microglial activation.[93, 94].

The S100 protein family is implicated in a variety of intra- and extracellular regulatory effects. They are localized both in the cytoplasm and in the nucleus of various cells [95]. An increase in S100B and the S100B receptor has been implicated in inflammation, which along with RAGE can activate microglia via NF-κB and AP-1-dependent pathways. Furthermore, an increase in S100B levels in biological fluids is also associated with brain damage [96]. Depending upon the concentration of S100B in the brain, it can exhibit neurotrophic or neurotoxic effects. In normal physiological conditions, low levels of S100B have been shown to decrease microglial activation via the STAT3 pathway with an upregulation of anti-inflammatory cytokines. Moreover, the clinical severity of bacterial meningitis appears to be related to the high concentration levels of S100B protein in the CSF [97]. The concentration of S100B in children with purulent meningitis was significantly higher than in the control group [98]. In rabbits with pneumococcal meningitis, the S100B protein was elevated and proposed to be a biomarker for the severity of white matter damage and traumatic injury by the authors of this study [99, 100].

Therapeutic Targets Through the Inhibition M1 or Activation M2 Microglia in Bacterial Meningitis

A more complete understanding of the association between bacterial meningitis and it’s pathophysiology is important in order to develop new therapeutic targets for the prevention of cognitive impairment [101].

HMGB1-antagonist

In a mouse meningitis model, treatment with an HMGB1-antagonist, ethyl pyruvate or Box A protein, decreased inflammation and neuronal damage in the brain when combined with ceftriaxone treatment [19]. Anti-HMGB1 monoclonal antibody also attenuated brain damage in a rat model of experimental brain trauma [20]. Because pro-inflammatory mediators contribute to meningitis-associated brain injury, HMGB-1 may be a promising target for (adjuvant) therapy [19].

Minocycline

Minocycline is a semisynthetic second generation tetracycline with anti-inflammatory effects on microglial cells, as well as antioxidant, anti-apoptotic, and neuroprotective properties in rodent models [102]. Its anti-inflammatory properties are represented by downregulation of microglial activity which is associated with decreasing cytokine and cyclooxygenase-2 expression and prostaglandin E2 production [103]. Minocycline has also been shown to reduce microglial and neuronal activation in the brain in experimental myocardial infarction [22] and in neonatal rats that received an intra-hippocampal injection of LPS [21]. Additionally, the activated state of microglia was prevented by minocycline in hypoxic-ischemia and hyperoxia animal models [23].

Resveratrol

Resveratrol is a non-flavonoid polyphenol that can attenuate the activation of immune cells through inhibition of NF-κB and activator protein-1 (AP-1) [104]. Resveratrol treatment preserved hippocampal neurons in rats after being infected with bacteria that causes meningitis. Increased microglial expression coincided with intense production of pro-inflammatory cytokines and oxidative damage; however, resveratrol treatment decreased microglial activation through Iba-1 expression which was associated with a decrease in pro-inflammatory cytokine levels and malondialdehyde (MDA) levels in the hippocampus [25].

Fractalkine

Fractalkine, or chemokine (C-X3-C motif) ligand 1 (CX3CL1), is a member of the ∂ (CX3C) chemokine family, and its receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), is found on the membrane of microglial cells. Fractalkine promotes microglial recruitment to neuronal circuits modulating neuronal survival via the release of trophic factors [26]. In addition, this chemokine activates microglia to rescue neurons by upregulating phagocytosis of toxicants or injured debris and promotes antioxidant enzyme production [16]. In patients with bacterial meningitis, CX3CR1 levels in the CSF were significantly increased when compared to levels in controls [105]. Alternatively, Fractalkine inhibits LPS-induced NO production and TNF-α release in primary neuron-glia cultures [27]. CX3CL1 knockout mice had microglial activation in different models of brain disease, including toxic insult by peripheral LPS injections [106].

Mesenchymal Cells

Mesenchymal stem or stromal cells (MSCs) are multipotent progenitor cells with regenerative and immunomodulatory properties [107]. MSC transplantation has been observed to attenuate brain damage after neonatal stroke [108]. MSC-mediated induction of the M2 phenotype through upregulation of Ym1 and Arg-1 mRNA levels restored neurological functions after experimental brain trauma [28].

IL-10

The anti-inflammatory cytokine IL-10 is secreted by microglia in the M2b state and is a powerful suppressor of pro-inflammation and is involved in neuronal regeneration and repair [72]; in vitro, IL-10 has also been shown to augment TGF-β production in astrocyte-microglia co-cultures. Inhibition of TGF-β production after LPS administration in mice prolonged sickness behavior and the pro-inflammatory state [29].

IL-34

IL-34 is a cytokine that stimulates the development, survival, and function of microglial cells [109]. This cytokine was identified as a second ligand for CSF-1R [110]. Additionally, IL-34 activates microglia to rescue neurons by upregulating phagocytosis of toxicants or damaged debris, and produces antioxidant enzymes [16].

Palmitoylethanolamide

Palmitoylethanolamide is an endogenous lipid produced by neurons, microglia, and astrocytes [111]. Pre-treatment with palmitoylethanolamide increased survival of mice challenged intracerebrally or intraperitoneally with Escherichia coli K1. In vitro, stimulation of macrophages with palmitoylethanolamide for 30 min increased the phagocytosis of E. coli K1 and S. pneumoniae [32, 112]. Palmitoylethanolamide increases phagocytosis of bacteria by microglial cells in vitro without a measurable pro-inflammatory effect. Therefore, this compound could be a promisor candidate against brain infections [113] (Table 4).

Table 4 Therapeutic/adjuvant treatments in experimental setting
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Conclusion

During bacterial meningitis, the severe inflammatory response may lead to neuronal damage and could potentially be detrimental for patients. Many stimuli including PAMPs, DAMPs, and pro-inflammatory mediators are responsible for the activation of microglia cells which further produce cytokines, chemokines, and reactive oxygen and nitrogen species to eliminate the invading microorganism. Therefore, the inhibition of pro-inflammatory mediators or the enhancement of anti-inflammatory mediator production in bacterial meningitis may be a useful strategy to prevent the devastating consequences of the bacterial infection with respect to neuronal damage and function. We propose that inhibition of the activity of DAMPs and/or administration of specific anti-inflammatory agents may lead to lower morbidity and mortality in patients with bacterial meningitis.