This thesis explored multiple aspects that are related to systemic inflammatory response syndrome (SIRS), a prevalent disease with a high mortality and a treatment that is mainly supportive. During SIRS, several cytokines, danger associated molecular patterns (DAMPs), matrix metalloproteinases (MMP), and other inflammatory mediators are induced that lead to the breakdown of brain barriers. Interestingly, our group previously showed that mice deficient for MMP8 are protected in different SIRS mouse models, which was reflected by the almost absence of brain barrier leakage. Therefore, considering the ability of Nanobodies (Nbs) to target the catalytic cleft of enzymes, it was decided to generate an MMP8-blocking Nb. The first part of this thesis includes the optimization of an MMP8-inhibiting Nb and its administration by in vivo electroporation to explore the therapeutic potential in systemic inflammation. We demonstrated that the Nb was able to inhibit its target, that we could modify it to improve avidity and pharmacokinetic properties, and that this led to protection in two different SIRS models. Since MMP8 also plays a detrimental role in other diseases, such as atherosclerosis, multiple sclerosis and bacterial meningitis, this Nb has a wide array of implications. In addition, we administered the Nb by in vivo electroporation of the muscle and showed that this approach can lead to a long production of Nb into the circulation. Although this approach may not be ideal for acute SIRS, it could be a novel way to administer Nbs in a more chronic disease setting. The hyperinflammatory reaction during SIRS is accompanied by an influx of leukocytes into the CNS, which leads to the worsening of the ongoing (neuro)inflammatory response. Literature regarding leukocyte infiltration across brain barriers during SIRS and its functional meaning is inconclusive. Therefore, the role of the choroid plexus (CP) as initial entry gate for leukocytes was explored in a second part. We found that leukocytes entered the cerebrospinal fluid (CSF) but not the brain parenchyma during SIRS. This suggests that leukocyte migration does not occur across the blood-brain barrier (BBB) but across the blood-cerebrospinal fluid barrier (BCSFB), which was indeed strengthened by flow cytometry data and immunofluorescent stainings. These observations could be important to identify new drug therapies that target this neuroinflammatory component of SIRS. Interestingly, we found some preliminary evidence that N-glycans at the CP are significantly changed during SIRS. As this aspect never has been investigated before, and considering the suggested importance of N-glycans in leukocyte adhesion, rolling and migration, this poses a very interesting field of investigation. SIRS stems from an imbalance in pro- and anti-inflammatory pathways that results into a hyperinflammatory state. A counter-reaction of the body to dampen this pro-inflammatory response is the compensatory anti-inflammatory response syndrome (CARS). CARS includes the production of anti-inflammatory cytokines and the anti-inflammatory neuroimmune axis that comprises the hypothalamic-pituitary adrenal (HPA) axis and vagus nerve. We were interested in the role of the vagus nerve in systemic inflammation, since its role remains unclear. Generally, vagus nerve stimulation (VNS) is considered protective, while vagotomy is suggested to be detrimental, but controversy persists. Hence, the third chapter of this thesis investigates the effect of unilateral cervical vagotomy in a sepsis model and sterile SIRS model. But in contrast to what is stated in existing literature, we found that unilateral vagotomy was protective in our setup. Moreover, we found some preliminary evidence that this could be due to the ability of the vagus nerve to modulate the HPA axis. Even though the rationale behind this project is not the use of vagotomy as therapy in patients, it does shed light on the possible mechanisms by which the vagus modulates the anti-inflammatory response during SIRS, which could lead to the identification of new targets. During SIRS, the neuroinflammatory component disturbs neurotransmitter balances, leading to several behavioral and cognitive deficits (e.g. confusion, agitation and changes in consciousness). This SIRS-associated encephalopathy (SE) occurs in a large portion of SIRS patients and is currently untreatable. Moreover, some sepsis survivors exhibit long-term cognitive defects such as problems with learning, memory and social behavior. A few studies in animal models were done to investigate the link between SIRS and cognitive dysfunction, but strong evidence is lacking and controversy persists. Thus, the last part of this thesis explored the long-term effect of sepsis on motor function and cognition in an endotoxemia mouse model. Our study could not prove the presence of cognitive dysfunction 4 weeks after recovery from an LPS-induced challenge. So, the cognitive dysfunction resulting after a SIRS episode is probably more strongly associated with other factors, such as age, comorbidities and genetic predisposition. Finally, mild traumatic brain injury (mTBI) is a common form of brain trauma that does not always require hospitalization. It can be induced by a fall or accident, but also by certain sports (e.g. boxing) or during the course of war (e.g. blast injury). Importantly, the biggest economic and social burden results from the lasting neurological sequelae post-trauma, such as cognitive problems (e.g. attention) and emotional deficits (e.g. depression). Moreover, TBI patients often have gastrointestinal (GI) problems and the administration of probiotics is suggested to be protective. So, a fifth and last chapter of this thesis is dedicated to the optimization of a weight drop model for mTBI, its influence on several inflammatory readouts (e.g. brain barrier leakage, systemic inflammation, corticosterone levels) and on the gut microbiome. We found that this mTBI model was associated with a very acute effect on the brain barrier, extracellular vesicles (EVs) in the CSF and microbiome. However, no prominent systemic inflammation nor neuroinflammation was present, which makes the significant change in microbiome a very interesting observation that should be explored. Further investigation on the role of the microbiome, bacterial metabolites and intestinal inflammation, in TBI could give new insights and could lead to the discovery of new drug targets that could improve or even prevent the debilitating consequences of TBI.