Guidelines as prescribed by PRISMA (Preferred reporting items for systematic reviews and meta-analyses) were followed while constructing this review (Liberati et al., 2009; Moher et al., 2009). The checklist items from PRISMA as relevant to this review, for example those related to search and writing approaches, were included and the items not relevant, for example those related to meta-analyses, were excluded.

Electronic database search of PubMed, ScienceDirect and Google Scholar was systematically performed from January-1988 to March-2017 using various combinations of the following keywords: glial cells, microglia, depression, brain, CNS, astrocytes, neurogenesis, neurodegeneration, neuroprotection, neuroinflammation, neuroregeneration, cytokines, IL, TNF, TGF, chemokines, CRP, cellular, humoral, immune, aging, Alzheimer's disease, cognition, behavior, metabolic disorders, diabetes, obesity, cardiovascular disease, cancer, systemic, tryptophan, inflammasomes, NLRP3, hippocampus, cerebral, frontal cortex, pathogen-associated molecular patterns, and damage associated molecular patterns. At each stage of the search, titles and abstracts were scrutinized, and the most appropriate of them were organized into separate folders using EndNote X6.0.1 software (Clarivate Analytics). Articles relevant to our discussion were also retrieved from the reference list of other online articles on each subtopic. All duplicate articles in EndNote were then deleted. Articles without the full text available and with anecdotal evidence were excluded from the review.

The process mentioned above of Article selection and deletion yielded 1,784 articles in total. After placing all inclusion and exclusion criteria into our search (as depicted in Figure 1), a total of 412 full-text manuscripts were short-listed for further analysis. Both human and rodent data were included. In the next stages, 206 studies were further excluded following exclusion criteria as per Figure 1. In all, 206 articles closely related to the aims set forth for this review were selected and hence utilized.

The various neuroimmune signaling pathways associated with microglial and microglia-derived cytokines activity in the brain and their association with depression have been critically analyzed in the current review. Hence the articles investigating immune functions of the microglia, their mechanism of actions during bidirectional communication between the nervous and immune systems and their association with depression were selected for detailed analysis.

Clinical depression seems to occur more commonly in people with certain risk factors (Kendler et al., 2006a). Besides external and environmental factors like substance abuse, lack of peer support, marital problems, low socioeconomic status, low education, and stressful life events; many of the internalizing factors play a major role as well. Significant among them are genetic alterations and acquired anatomical defects. Certain genetic subgroups are more vulnerable to developing depression, and monozygotic twins show a concordance rate of almost 40% for developing MDD (Sullivan et al., 2000; Kendler et al., 2006b). In spite of observed anatomic and physiologic changes in brain, no conclusive proof has been found linking any combination of genetic and environmental factors (aan het Rot et al., 2009; Risch et al., 2009). The altered levels in certain growth factors and neurotransmitters such as serotonin, norepinephrine, dopamine, GABA, brain-derived neurotrophic factor (BDNF), glutamate, cannabinoid (CB1) receptors, acetylcholine, and substance P have been proven time and again to cause depression and the protocols for treating depression have been developed to maintain those imbalances (Duman et al., 1997; Svenningsson et al., 2006; Thase, 2007; Hill and Gorzalka, 2009). Also, factors like over and under activity of hypothalamic-pituitary-adrenal axis may also be responsible for MDD (Gillespie and Nemeroff, 2005; Vreeburg et al., 2009). However, researchers have found that these functional causes go hand-in-hand with anatomic alterations at the cellular level (Rajkowska and Miguel-Hidalgo, 2007).

Several anatomical changes are related to depression as detected in magnetic resonance studies of the brain (Koolschijn et al., 2009). Some of the consistent findings are decreased lobar volumes, especially frontal, temporal, and hippocampal volumes and higher volumes of ventricles on overall brain volume (Lampe et al., 2003; Taylor et al., 2007). There is a significant loss of GABAergic neurons in occipital, prefrontal and limbic regions and size of neurons are decreased by one-fifth (Cotter et al., 2001, 2002; Rajkowska et al., 2007; MacIag et al., 2010). Significant changes are noted in the number, density and size of glial cells during MDD (Ye et al., 2011). These evidences suggest the role of glial cells in mood disorders and the potential part played in the pathogenesis of the latter. We, however, limit our discussion to microglia among the glial cell population and their effects post activation leading to depression in this review.

Microglia overexpress proinflammatory cytokines in the CNS in response to adverse stimuli, such as psychological stress (Avitsur et al., 2005; You et al., 2011), age (Kumagai et al., 2007), metabolic disorders (Volpato et al., 2001; Il'yasova et al., 2005; De Rekeneire et al., 2006; Stannus et al., 2013), traumatic brain injuries (Fenn et al., 2014), or infections (Dunn, 2006). This results in neuroinflammation, leading to an imbalance of several brain functions, some of them being the characteristics of MDD as per DSM-V, such as low mood, insomnia, fatigue and change in appetite (Maes et al., 1997; Howren et al., 2009; Dowlati et al., 2010; Hannestad et al., 2011). A recently conducted study has shown that microglia get primed with MHC II complex and overexpress proinflammatory cytokines even post 30 days after traumatic brain injury in BALB/c mice. These changes in microglial morphology has been found to be associated with depressive-like behavior (Fenn et al., 2014). A meta-analysis reported high concentrations of the proinflammatory cytokines TNF-α and IL-1β and IL-6 in depressed subjects than controlled subjects (Dowlati et al., 2010). These findings are consistent with the previously published reviews and may be associated with the hyperactivity of microglia in the brain (Hanisch, 2002; Schroeter et al., 2008; Smith et al., 2012). TNF-α produced in response to microglial hyperactivity causes hippocampal degeneration and microglial apoptosis (Cacci et al., 2005), the former being a characteristic finding in patients with unipolar depression (Videbech and Ravnkilde, 2015). In addition, IFN-α promotes expression of proinflammatory surface markers MHC II, CD86, and CD54 indicating M1 polarization, thus leading to neuroinflammation and depression (Wachholz et al., 2016). All above pathways associate alterations in microglial morphology and activity to neuroinflammation which subsequently lead to the development of depression.

Contrary to above, when the inflammatory response is blocked with external non-steroidal anti-inflammatory factors, such as Indomethacin and Ibuprofen, and with fusion proteins produced from recombinant DNA, such as Etanercept that inhibits microglial TNF expression (lou Camara et al., 2015), a considerable improvement in neurogenesis (Monje et al., 2003) and a reduction in depressive-like behavior (Iyengar et al., 2013) has been reported. Antidepressants such as imipramine and minocycline reduce proinflammatory cytokines levels by inhibiting microglial proliferation and activation, and subsequently attenuate depressive-like symptoms (Tikka et al., 2001; Fischer et al., 2015; Zheng et al., 2015). Imipramine has been shown to reduce the number of chronic stress induced- activated hippocampal microglia (Iwata et al., 2016), perhaps by selectively inhibiting the M1 polarization of microglia (Kobayashi et al., 2013). Similarly, another antidepressant, pioglitazone acts by inhibiting the increased numbers and microglial morphological alterations in the hippocampus, reducing the overexpressing microglial M1 markers and increasing the under-expressed microglial M2 markers in C57BL/6 mice exposed to chronic mild stress (Zhao et al., 2016). Another technique involves using transgenic proinflammatory cytokines receptor antagonists, such as IL-1 receptor antagonist that reduces microglial apoptosis and subsequently neuroinflammation and depressive-like behavior in rodents (Goshen et al., 2008; Koo and Duman, 2009; Kreisel et al., 2014a). Neuroinflammation, therefore, is one of the main etiological factor for depression and most currently available treatments for depression alter the related pathways, in turn, alleviating inflammation in brain.

The inflammasomes hypotheses of depression and its comorbidity with systemic illnesses have been reviewed elsewhere (Iwata et al., 2013; Singhal et al., 2014). Inflammasomes are cytosolic protein complexes which when assembled and activated in the presence of PAMPs and DAMPs, further activate proinflammatory caspases, in particular, caspase-1. Caspase 1 subsequently splits inactive forms of proinflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms (Arend et al., 2008; Chakraborty et al., 2010) causing neuroinflammation (Davis et al., 2011) which is the leading etiology of depression as mentioned previously (Walker et al., 2014). The role of microglia is important in the activation of inflammasomes as they carry pattern recognition receptors (PRRs) that function to recognize PAMPs and DAMPs. While PRRs can be membrane bound (toll-like receptors) or localized within the cytoplasm Nod-like receptors (NLRs), it is the NLRs which when activated lead to the assembly and activation of inflammasomes in the cytoplasm (Arend et al., 2008; Chakraborty et al., 2010). Of all inflammasomes, NLRP (Nod-like receptor family, containing pyrin domain) inflammasomes have been primarily implicated in the etiology of depression (Zhang Y. et al., 2014; Ghisleni, 2017; Kaufmann et al., 2017). The microglial membrane is rich in purinergic receptor P2X7 which when activated with chronic stress subsequently activates NLRP3 inflammasome in hippocampal microglia augmenting proinflammatory environment in the CNS (Yue et al., 2017). A study has confirmed the role of NLRP3 inflammasomes in lipopolysaccharide (LPS)-induced depressive-like behavior in mice (Zhang Y. et al., 2014). Similar findings were seen in human participants when activated NLRP3 inflammasomes were detected in blood mononuclear cells from depressive patients (Alcocer-Gómez et al., 2013). Interestingly, TNF-α has also been shown to trigger the activation of caspase 1 and in turn secretion of IL-1β from microglia (Alvarez and Munoz-Fernandez, 2013), further aggravating neuroinflammation. Interestingly, it has been suggested that inflammasome-related inflammation is an ongoing process in psychiatric patients during disease states (Hohmann et al., 2014).

The finding that mice lacking caspase-1 are resistant to LPS-induced depressive-like behavior further supports the above inflammasome hypotheses for depression (Moon et al., 2009). Based on this, targeted therapies such as antidepressants like fluoxetine which alleviate depression by inhibiting the peripheral and central NLRP3 inflammasome activation have been developed (Du et al., 2016). Chrysophanol also exerts similar effects, however by inhibiting P2X7 pathway (Zhang et al., 2016), and hence plausibly the subsequent activation of NLRP3 inflammasome as mentioned earlier.

Increased levels of systemic proinflammatory cytokines and acute phase proteins (e.g., C-reactive protein) have been reported in chronic inflammatory diseases such as cancer (Il'yasova et al., 2005), diabetes (De Rekeneire et al., 2006), osteoarthritis (Stannus et al., 2013), and cardiovascular disease (Volpato et al., 2001) in aged cohorts. An association between age-related depression and level of proinflammatory cytokines in the brain has also been established (Godbout et al., 2008). These findings hint to a possible mechanism whereby proinflammatory cytokines and acute phase proteins play a crucial role in the comorbidity of systemic diseases with depression, especially during old age. To support this hypothesis, a look back is required into a previously published review describing various pathways for the transport of proinflammatory cytokines to brain from systemic circulation (Capuron and Miller, 2011). In one of the pathways, cellular pathway, TNF-α secreted from activated monocytes and macrophages migrates to brain through BBB and stimulates microglia to produce MCP-1, in turn recruiting monocytes into the brain. Also, increased production and expression of IL-1β in the brain after LPS-induced systemic inflammation (Cunningham et al., 2005) and changes in mood and behavior similar to depression after systemic administration of proinflammatory cytokines (Pollak and Yirmiya, 2002) has been reported in rodents. Given that metabolic disorders can predispose to the development of psychiatric disorders, it is possible that inflammasome-driven inflammatory pathways in the cytoplasm of microglia may be a potential mechanism driving this co-morbidity as these pathways have been shown to be associated with the development of Type II diabetes (Grant and Dixit, 2013; Lee et al., 2013), obesity (Stienstra et al., 2011), and cardiovascular diseases (Garg, 2011), as well as cancer (Zitvogel et al., 2012). The activation of inflammasomes in microglia, particularly NLRP3, therefore could be indirectly related to the pathophysiology of depression and its comorbidity with other systemic diseases through an inflammatory response in the brain.

Recent studies have established a causal relationship between the stress-related life events/chronic stress and depressive-like behavior in mice (Goshen et al., 2008; Berry et al., 2012). Indeed, chronic unpredictable mild stress (CUMS) has been shown to cause neuroinflammation and subsequently depression in several studies (Farooq et al., 2012; Ramirez et al., 2016; Tong et al., 2017). Microglial dysfunction has been implicated in chronic unpredictable stress-induced neuroinflammation and depression-like condition in rodents (Kreisel et al., 2014a). In a study, the initial phase of stress stimulation induced microglial proliferation and activation while prolonged stress resulted in microglial apoptosis leading to a reduction in their numbers, reduced expression of activation markers and dystrophic morphology in the hippocampus (Kreisel et al., 2014a). Microglia have been shown to get hyper-ramified during chronic stress leading to depression (Hellwig et al., 2016). It is interesting to note that microglial increase in numbers and transition from a ramified-resting state to a non-resting hyper-ramified state is more in certain stress-sensitive brain regions in response to the chronic stress (Tynan et al., 2010). Indeed, repeated chronic stress increased numbers of hyper-ramified microglia in the hippocampus, prefrontal cortex, amygdala, and nucleus accumbens (Bian et al., 2012; Farooq et al., 2012; Wohleb et al., 2012; Kopp et al., 2013). Hyperactivated microglia produce excessive proinflammatory cytokines, show enhanced antigen presentation and become increasingly phagocytic (De Pablos et al., 2006; Bradesi et al., 2009; Giovanoli et al., 2013; Lehmann et al., 2016). In addition, microglial response to stress proteins is guided by their glucocorticoids receptors (Frank et al., 2012) and nor-adrenaline activated alpha/beta-adrenergic receptor signaling pathways (Blandino et al., 2006). For example, stress hormones down-regulate glucocorticoids receptors which further declines microglial response to the stress proteins (Reichardt et al., 2001; Cohen et al., 2012). Similarly, a decline in the secretions of proinflammatory cytokines from microglia has been reported in response to nor adrenaline-activated alpha/beta-adrenergic receptor signaling pathways (Mori et al., 2002; Russo et al., 2004; Färber et al., 2005; O'Sullivan et al., 2009).

Evidently, few antidepressants have been shown to exert anti-depressive effects by restoring microglial morphology to the resting stage. For example, chronic treatment with the antidepressant venlafaxine restored microglia morphology and reduced depression-like behavior (Hellwig et al., 2016). Likewise, blocking of initial proliferation and activation of microglia in response to CUMS using antidepressants minocycline and imipramine prevented subsequent apoptosis and morphological distortions of microglia and hence depressive behavior (Kreisel et al., 2014a).

Many recent studies have found a link between MDD and activation of the enzymes indoleamine 2, 3-dioxygenase (IDO), and signaling via the kynurenine pathway (KP) (Dantzer, 2016; Parrott et al., 2016; Liu et al., 2017). Microglial IDO is activated by inflammatory cytokines like IL-6, TNFα, IFN-γ, and their inducers like LPS and HIV Tat protein (Dantzer et al., 2011; Walker et al., 2013). The involvement of the microglial KP in mediating inflammation and stress-induced depression is supported by clinical studies demonstrating that IFN-α immunotherapy increases tryptophan metabolism through the KP pathway, both in periphery and CSF, and this increase is significantly correlated with the development and severity of IFN-α-induced depression (Capuron et al., 2003). A recent clinical trial investigated cerebral tryptophan metabolism in brain-tumor associated depression and established that abnormalities in tryptophan transport and metabolism in the thalamus, striatum, and frontal cortex are associated with depression in patients which may, in turn, indicate an imbalance between the serotonin and kynurenine pathways (Bosnyák et al., 2015). Although, research in this direction is still in infancy stage, altering tryptophan metabolism pathways has shown good potential in treating depression in recent times (Abildgaard et al., 2017; Eskelund et al., 2017).

Microglia are known to modulate the production of neurotrophins, mainly BDNF (Ferrini and De Koninck, 2013), a protein known for regulating neurogenesis in the dentate gyrus of the hippocampus (Rossi et al., 2006; Fan et al., 2007) and enhancing dendritic branching (McAllister et al., 1995; Horch and Katz, 2002; Horch, 2004). It is widely known to be associated with hippocampal plasticity (Ye et al., 2011). Neurotrophin deficiency in the presence of dystrophic microglia may therefore hinder hippocampal neurogenesis and further precipitate depressive-like symptoms.

BDNF infusion is seen to partially reverse the effect of the chronic stress-induced depressive behavior in a rat model (Ye et al., 2011). The use of Gastrodin and total glycosides of peony (TGP), both of which are Chinese herbs used to treat depression, as well as the antidepressants like imipramine and fluoxetine are seen to up-regulate the hippocampal BDNF mRNA expression (Mao et al., 2010; Takano et al., 2012; Quesseveur et al., 2013; Zhang R. et al., 2014). On the other hand, an overexpression of BDNF also has an anxiolytic effect and promotes local neurogenesis (Quesseveur et al., 2013). Similar effects of these drugs are seen on the up-regulation of Glial Cell Line-derived Neurotrophic Factor (GDNF) (Hisaoka-Nakashima et al., 2015). The role of GDNF in depression was further supported by lower serum GDNF concentrations in MDD patients as compared to controls (Zhang et al., 2008).

The role of microglia in hippocampal neurogenesis has been discussed many times in the past, and hence we have limited our discussion to few important points on this topic for the purpose of this review. Impaired hippocampal neurogenesis has been shown to be an important underlying cause of depression (Jacobs et al., 2000). Numerous studies have reported that microglia activation plays a key role in suppression of hippocampal neurogenesis under conditions of stress and inflammation (Kempermann and Neumann, 2003; Sierra et al., 2014). Studies on mice have shown that irradiation or treatment with lipopolysaccharide causes marked suppression of hippocampal neurogenesis, while treatment with minocycline negated this effect (Ekdahl et al., 2003; Monje et al., 2003). Interestingly, neurogenesis suppression in response to microglial activation was primarily due to the detrimental effect on maintenance of newborn neurons rather than on their proliferation (Ekdahl et al., 2003; Monje et al., 2003). Further, in-vitro experiments have shown that the conditioned media from LPS-challenged microglia induced IL-6 or TNFα-mediated apoptosis in hippocampal neuroblasts (Monje et al., 2003; Cacci et al., 2005). These findings therefore suggest that hippocampal neurogenesis is affected by the microglial activation status. Although, hippocampal degeneration has been shown to result primarily in response to chronic neuroinflammation during aging, the exact mechanism for the same is still not elucidated.

Recent evidence has confirmed that both over expressed and under expressed microglia can cause depression. While over expressed microglia trigger the onset of depression through the neuroinflammatory pathway as mentioned before, under expressed microglia could result in depression through hippocampal degeneration pathway. Chronic form of stressors, for example chronic unpredictable stress, chronic restraint stress, and chronic social defeat stress have all lead to depression through reduction in the number of hippocampal microglia (Tong et al., 2017). On the other hand, rats exposed to learned helplessness showed increase in the number of activated microglia in the granule cell layer, hilus, CA1, and CA3 regions of the hippocampus (Iwata et al., 2016). Overall, this suggests that both the under expression and over expression of microglia in brain lead to depression albeit through different molecular pathways. As such, altering these molecular pathways associated with microglial activity through pharmacological and non-pharmacological means could provide a novel therapeutic intervention for depression.

Indeed, some recent studies have shown that treatment with antidepressants Imipramine or Minocycline decreases IFN-γ levels by inhibiting microglial activation and subsequently reduces the depressive symptoms in animal models of depression (Fischer et al., 2015; Zheng et al., 2015). Studies involving a transgenic IL-1 receptor antagonist have shown to reduce microglial apoptosis and subsequently neuroinflammation and depressive-like behavior in rodents (Goshen et al., 2008; Koo and Duman, 2009; Kreisel et al., 2014a). Similarly, Etanercept, known to reduce depression associated with rheumatoid arthritis and psoriasis (Tyring et al., 2006; Kekow et al., 2009), has been shown to inhibit microglial TNF expression and reduce brain inflammation in C57BL/6 mice (lou Camara et al., 2015). These results clearly demonstrate the recent developments in microglia targeted therapies for depression.

More recently, the role of gut microbiota on the brain development, immunomodulation and change in behavior has attracted attention of researchers. While gut lining is impermeable to toxic substances, any microdamage to it could increase the permeability and movement of micro molecules both ways (Turner, 2009). Microorganisms, such as firmicutes, bacteroidetes, actinobacteria, and proteobacteria, that live in the intestine (Ley et al., 2006) interact with immune cells through the permeable mucosal lining forming bidirectional communication between the brain and the gut (Mayer, 2011). TLRs on the gut lining play a vital role in the initiation of this communication and passing the immune message to the brain (Zeuthen et al., 2008). Recent evidence has established the role of gut microbiota in the development of depression, perhaps through the production of neuroactive substances such as serotonin, nor-epinephrine, dopamine, and gamma-aminobutyric acid, which act on the gut-brain axis (Dinan and Cryan, 2013). Interestingly, current antibiotics treatment for infections, as well as vaccinations have been shown to affect the integrity of gut microbiome (Evrensel and Ceylan, 2015). If this has any effect on the development of depression is however still not established. In addition, stress can also influence the diversity of gut microbiota, for example decrease in the levels of fecal Lactobacillus was observed in rats separated from their mother (O'Mahony et al., 2009).

As we discussed above, change in microglial morphology and activity is hugely responsible for the onset of depression. Until recently, it was however not known if gut microbiota has any effect on microglia and associated development of depression. However, a research from Erny et al. has provided evidence for the role of gut microbiota in depression through modulation of microglial associated immune network. Researchers observed that germ free mice showed defects in microglial functions as well as reduction in their numbers, leading to impaired immune response affecting neural circuitry, a potential factor for the onset of depression (Erny et al., 2015). This overall suggest that gut microbiota has a role in the onset of depression, especially during early age, through the alteration of microglial activity in brain. However, further research is required to establish this hypothesis.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.