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Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis

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Abstract

Bacterial meningitis is a life-threatening infection associated with cognitive impairment in many survivors. The pathogen invades the central nervous system (CNS) by penetrating through the luminal side of the cerebral endothelium, which is an integral part of the blood-brain barrier. The replication of bacteria within the subarachnoid space occurs concomitantly with the release of their compounds that are highly immunogenic. These compounds known as pathogen-associated molecular patterns (PAMPs) may lead to both an increase in the inflammatory response in the host and also microglial activation. Microglia are the resident macrophages of the CNS which, when activated, can trigger a host of immunological pathways. Classical activation increases the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species, while alternative activation is implicated in the inhibition of inflammation and restoration of homeostasis. The inflammatory response from classical microglial activation can facilitate the elimination of invasive microorganisms; however, excessive or extended microglial activation can result in neuronal damage and eventually cell death. This review aims to discuss the role of microglia in the pathophysiology of bacterial meningitis as well as the process of microglial activation by PAMPs and by endogenous constituents that are normally released from damaged cells known as danger-associated molecular patterns (DAMPs).

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Abbreviations

17β‑HSD14:

17β‑hydroxysteroid dehydrogenase type 14

AIM2:

Absent in melanoma

AP-1:

Activator protein-1

Arg1:

Arginase 1

ASC:

Apoptosis-associated speck-like protein containing a caspase-recruitment domain

ATP:

Adenosine 5′-triphosphate

BBB:

Blood-brain-barrier

CLRs:

c-type lectin receptors

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CX3CL1:

Chemokine (C-X3-C motif) ligand 1

CX3CR1:

Chemokine (C-X3-C motif) receptor 1

DAMPs:

Damage-associated molecular patterns

DHEA:

Dehydroepiandrosterone

DNA:

Deoxyribonucleic acid

ERβ:

Estrogen receptor beta

FIZZ1:

Found in inflammatory zone 1

GSA-IB4:

Griffonia simplicifolia isolectin-B4

HMGB-1:

High mobility group box-1 protein

HSP:

Heat shock protein

Iba1:

Ionized calcium binding adaptor molecule 1

IFN:

Interferon

IGF-1:

Insulin-like growth factor 1

IL:

Interleukin

iNOs:

Nitric oxide synthase

IRAK-4:

Interleukin-1 receptor-associated kinase 4

IRF-3:

Interferon-regulatory factor 3

JAK-1:

Receptor-Janus Kinase-1

LPS:

Lipopolysaccharide

M1:

Classical activation phenotype

M2:

Alternative activation phenotype

MDA:

Malondialdehyde

MIP-2:

Macrophage inflammatory protein 2

MyD88:

Myeloid differentiation factor 88

NF-κB:

Nuclear transcription factor kappa factor B

NLRP3:

Nucleotide-binding domain and leucine-rich repeat protein 3

NLRs:

Nucleotide binding oligomerization domain-like receptors

NO:

Nitric oxide

NODs:

Nucleotide binding oligomerization domains

O2 − :

Superoxide anion

ONOO− :

Peroxynitrite formation

P2X:

P2 purinergic receptor

PAMPs:

Pathogen-associated molecular patterns

PRRs:

Pattern-recognition receptors

RAGE:

Receptor for advanced glycation end products

RLRs:

RIG-I-like receptors

STAT-3:

Activator of transcription-3

TGF-β:

Transforming growth factor beta

TLRs:

Toll-like receptors

TNF:

Tumor necrosis factor

TRAF:

Receptor-associated factor

TRIF:

TIR-domain-containing adapter-inducing interferon-β

Ym1:

Chitinase-3-like protein 3

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Acknowledgments

Research from the Center for Experimental Models in Psychiatry (USA) is supported by grants from the Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston. Research from Laboratorio de Microbiologia Experimental and Laboratório de Neurociências (Brazil) is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), and Universidade do Extremo Sul Catarinense (UNESC).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA

    Tatiana Barichello, Tatiana Barichello, Fabricia Petronilho, Priyanka Saigal, Marwa Badawy & João Quevedo

  2. Laboratory of Experimental Microbiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil

    Tatiana Barichello, Jaqueline S. Generoso, Lutiana R. Simões & Jessica A. Goularte

  3. Laboratory of Clinical and Experimental Pathophysiology, Graduate Program in Health Sciences, University of South Santa. Catarina, Tubarão, SC, Brazil

    Fabricia Petronilho

  4. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil

    João Quevedo

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  1. Tatiana Barichello
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  2. Jaqueline S. Generoso
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Correspondence to Tatiana Barichello.

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Barichello, T., Generoso, J.S., Simões, L.R. et al. Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis. Mol Neurobiol 53, 1770–1781 (2016). https://doi.org/10.1007/s12035-015-9107-4

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  • DOI: https://doi.org/10.1007/s12035-015-9107-4

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