Table 2.

Routes for Pathobiological Substance Entry into the Brain.

Routes	Mechanisms	References
Direct bacterial invasion	Bacteria and bacterial lipopolysaccharides can reach the CNS and activate matrix metalloproteases, which disrupt the BBB, increasing its permeability and allowing bacteria to penetrate the brain parenchyma.	Systemic route (Wright et al. 2007; Frister et al. 2014)
	Pathogenic bacteria can enter the brain through the peripheral nerve route such as the olfactory and trigeminal nerves.	Cranial route (Riviere et al. 2002; Olsen and Singhrao 2015)
Invasion of proinflammatory cytokines	The peripheral proinflammatory cytokines can activate the vagus nerve, which then relays the information to the CNS.	Neural pathways (Capuron and Miller 2011)
	The inflammatory mediators can enter the cerebral parenchyma and initiate the inflammatory response through the region of the brain that lacks the BBB, like the choroid plexus and circumventricular organs.	Humoral pathways (D’Mello and Swain 2017)
	Activated peripheral monocytes can be actively recruited by the chemokine system into the brain parenchyma, where they secrete proinflammatory cytokines, such as TNF-α, which activate microglia, leading to neuroinflammation.	Cellular pathways (D’Mello and Swain 2017)
Indirect communication	Leptomeningeal cells, present in the innermost layer of the meninges, transduce the peripheral inflammatory signals from macrophages to microglia in the brain via Toll-like receptor 2.	Leptomeningeal cells (Wu et al. 2005; Liu et al. 2013)

BBB, blood–brain barrier; CNS, central nervous system; TNF-α, tumor necrosis factor α.