**4. The interplay between mitochondria and innate immunity**

In response to microbial infection, the mammalian innate immune system recognizes invading microorganisms and orchestrates a proinflammatory immune response to eliminate the undesired pathogens and infected cells. The sensing of the infection by the innate immune system is mediated by a variety of pattern recognition receptors (PRRs), which recognize molecular patterns conserved among microbial species known as PAMPs. For detailed information regarding the different families of receptors, respective PAMPs recognition, and the intracellular signaling cascades triggered, see reference [288]. Interestingly, even in the absence of microbial infection, PRRs sense and orchestrate inflammatory responses through recognition of intracellular molecules known as DAMPs. DAMPs are endogenous molecules sequestered within cellular compartments of healthy cells, which, upon injury or stress, are released to trigger sterile proinflammatory immune responses.

Despite the great number of studies describing mitochondria as a source of DAMPs during inflammation in the periphery, the potential for mitochondrial DAMPs to trigger, or exacerbate, inflammation in the brain is now being explored. In recent studies, this potential was tested by treating different brain cell types with mitochondrial components and measuring markers of inflammation afterwards. Neuronal and microglial cell lines exposed to mitochondrial lysates displayed increased markers of inflammation, with mtDNA being identified as the candidate DAMP responsible for the inflammatory changes [95]. While SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFα mRNA, decreased IκBα protein and increased NF-κB protein, microglial cells treated with mitochondrial lysates showed increased TNFα mRNA, increased IL-8 mRNA and redistribution of NF-κB to the nucleus [95]. In a different study, extracellular recombinant Tfam treatment of different models of human microglia, in combination with IFN-ϒ, was shown to induce secretions that were toxic to SH-SY5Y neuronal cells [302]. Recombinant Tfam treatment induced the expression of proinflammatory cytokines, such as IL-1β, IL-6 and IL-18, supporting the hypothesis that Tfam may also act as a proinflammatory intercellular signaling molecule recognized by brain microglia [302]. Moreover, mice injected with isolated mitochondria into the brain also revealed increased markers of inflammation such as increased Tnfα, increased NF-κB phosphorylation, increased GFAP protein and decreased Trem2 mRNA [94]. Despite these novel findings describing a role for extracellular mitochondrial DAMPs as proinflammatory signaling molecules in the brain, little is known about the mechanisms by which mitochondria act as a transcellular signaling platforms in the CNS. Recent research revealed that neurons and astrocytes can exchange mitochondria as a potential mode of cell-to-cell signaling [303, 304]. Whilean initial study showed that retinal ganglion cell axons can transfer mitochondria to adjacent astrocytes for degradation [303], mitochondria can also be transferred from astrocytes to adjacent neurons during ischemia to amplify cell survival signals [304], thus representing a neuroprotective strategy or a more efficient way to dispose/recycle mitochondria. However, during neurodegeneration, increased disposal of damaged mitochondria by compromised neurons (e.g. due to compromised mitochondrial quality control mechanisms) or its inefficient uptake by the recipient astrocytes (e.g. due to the presence of extracellular protein aggregates) might result in extracellular accumulation of mitochondrial DAMPs and, as a result, exacerbating neuroinflammation. Further research is necessary to test this hypothesis and identify the PRRs in the brain that are responsible for recognizing extracellular mitochondrial DAMPs; nevertheless, these studies suggest that mitochondria play an active role in neuroglial cross-

Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer's and Parkinson's Diseases

http://dx.doi.org/10.5772/intechopen.72612

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Although the innate immune system has specialized in the recognition of molecular patterns foreign to the host cells, cellular injury or stress may result in the release of endogenous molecular patterns, which trigger sterile inflammatory responses. Given its bacterial origin, mitochondria display some similarities with bacteria and represent an important source of DAMPs (including lipids, nucleic acids and proteins) with immunostimulatory potential. While under healthy conditions these DAMPs are sequestered within mitochondria, pathological insults resulting in mitochondrial and cellular damage promote the release of these

talk during cellular homeostasis and stress.

**5. Concluding comments**

Recent insights revealed that mitochondria are an important source of DAMPs. Interestingly, upon injury, both mtDNA and N-formylated peptides can act as DAMPs. This is due to the fact that mitochondria and bacteria display some similarities in that both possess circular DNA, N-formylated proteins and are double-membrane structures—evidence used in support of the endosymbiotic theory. mtDNA is similar to bacterial DNA in that it contains CpG motifs, which activate the TLR9 [289, 290]. Moreover, mitochondrial protein synthesis is initiated with the residue N-formyl methionine, similar to bacterial protein synthesis [291]. The resulting bacterial N-formylated peptides are known to act as PAMPs by binding and activating G protein-coupled formyl peptide receptors (FPRs) [292], while the mitochondrial N-formylated peptides act as DAMPs through activation of the formyl peptide receptor 1 [290]. Therefore, upon injury, release of these mitochondrial DAMPs activates the innate immune system, much like bacterial PAMPs, to promote sterile inflammatory responses [290].

Several studies have now described a crucial role for mitochondria in the regulation and activation of the inflammasome, specifically the NLRP3 inflammasome [293]. The inflammasomes are intracellular molecular platforms activated upon cellular infection or sterile stressors, which activate the proinflammatory cytokines, interleukin-1β (IL-1β) and IL-18, to trigger pyroptotic cell death (reviewed in [294, 295]). A variety of insults, resulting from cellular infection or stress, can promote mitochondrial dysfunction and activate the NLRP3 inflammasome [293]; however, the molecular mechanisms underlying the contribution of mitochondria to the activation of the NLRP3 inflammasome have only recently been described. While initial studies showed that mitochondrial dysfunction and mtROS production are required for NLRP3 inflammasome activation [296, 297], further evidence has shown that mtDNA translocation to the cytosol plays an active role in this process [297, 298], where it can directly bind to and activate the NRLP3 inflammasome [298]. In addition, the mitochondrial lipid cardiolipin—a phospholipid located exclusively in mitochondrial inner and bacterial membranes, regarded as evidence for symbiogenesis [299, 300]—is also required for NLRP3 inflammasome activation, by directly binding to NLRP3, downstream of mitochondrial dysfunction [301]. Altogether, mitochondria and mitochondrial DAMPs (such as mtDNA and cardiolipin) play a critical role in NLRP3 inflammasome activation and regulation. Moreover, by sensing mitochondrial DAMPs, the NLRP3 inflammasome plays a critical role in integrating mitochondrial dysfunction in a proinflammatory signaling response, thus explaining the association of mitochondrial damage with inflammatory diseases.

Despite the great number of studies describing mitochondria as a source of DAMPs during inflammation in the periphery, the potential for mitochondrial DAMPs to trigger, or exacerbate, inflammation in the brain is now being explored. In recent studies, this potential was tested by treating different brain cell types with mitochondrial components and measuring markers of inflammation afterwards. Neuronal and microglial cell lines exposed to mitochondrial lysates displayed increased markers of inflammation, with mtDNA being identified as the candidate DAMP responsible for the inflammatory changes [95]. While SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFα mRNA, decreased IκBα protein and increased NF-κB protein, microglial cells treated with mitochondrial lysates showed increased TNFα mRNA, increased IL-8 mRNA and redistribution of NF-κB to the nucleus [95]. In a different study, extracellular recombinant Tfam treatment of different models of human microglia, in combination with IFN-ϒ, was shown to induce secretions that were toxic to SH-SY5Y neuronal cells [302]. Recombinant Tfam treatment induced the expression of proinflammatory cytokines, such as IL-1β, IL-6 and IL-18, supporting the hypothesis that Tfam may also act as a proinflammatory intercellular signaling molecule recognized by brain microglia [302]. Moreover, mice injected with isolated mitochondria into the brain also revealed increased markers of inflammation such as increased Tnfα, increased NF-κB phosphorylation, increased GFAP protein and decreased Trem2 mRNA [94]. Despite these novel findings describing a role for extracellular mitochondrial DAMPs as proinflammatory signaling molecules in the brain, little is known about the mechanisms by which mitochondria act as a transcellular signaling platforms in the CNS. Recent research revealed that neurons and astrocytes can exchange mitochondria as a potential mode of cell-to-cell signaling [303, 304]. Whilean initial study showed that retinal ganglion cell axons can transfer mitochondria to adjacent astrocytes for degradation [303], mitochondria can also be transferred from astrocytes to adjacent neurons during ischemia to amplify cell survival signals [304], thus representing a neuroprotective strategy or a more efficient way to dispose/recycle mitochondria. However, during neurodegeneration, increased disposal of damaged mitochondria by compromised neurons (e.g. due to compromised mitochondrial quality control mechanisms) or its inefficient uptake by the recipient astrocytes (e.g. due to the presence of extracellular protein aggregates) might result in extracellular accumulation of mitochondrial DAMPs and, as a result, exacerbating neuroinflammation. Further research is necessary to test this hypothesis and identify the PRRs in the brain that are responsible for recognizing extracellular mitochondrial DAMPs; nevertheless, these studies suggest that mitochondria play an active role in neuroglial crosstalk during cellular homeostasis and stress.
